Development, Structure, and Function of Hair Follicles and Hair-associated Disorders: Insights from Men and Mouse

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Development, structure, and function of hair follicles and hair-associated disorders: Insights from men and mouse


Hair is a remarkable entity with diverse functions in mammals. Over the past many years, hair loss has been a prime anxiety afflicting men. Since then, understanding the biology of hair has laid the foundations for the growth of a multibillion-dollar pharmaceutical/cosmetic industry. Changing dietary patterns, poor interaction with surroundings, and a resulting passive lifestyle has rendered modern society to accrue several factors which have been implicated in hair loss. Besides, genetic composition is considered as one of the most significant factors to determine hair structure, size, color, quality, distribution etc. Here we review the development, morphology, structure and functional aspects of hair shaft and hair follicles and the underlying molecular signalling mechanisms. We have focused on genetic disorders that cause hair loss in mouse and men. This information is valuable for the development of strategies to treat hair loss disorders and to research personnel working on epidermal appendage development.

Hair: minor significance or major impact?

“Hair,” which is thought to be of superficial value, indeed has several crucial functions. It provides thermal regulation in mammals [1], offers protection against several agents including ultraviolet radiation, dust, airborne debris and bugs (eg. hairs of the skin, eye, nose and ear) and maintains the functioning of sensory organs  (hairs in the auditory canal participate in hearing, hairs on the skin acts as a peripheral sensor of touch) [2, 3]. Further, hair acts as an indication of warning or mating by communicative displays to neighbours or opposite gender, respectively, enhances the physical appearance, and reflects reproductive maturity with respect to development of secondary sexual hairs [4] Under certain circumstances, hair acts as an indicator of clan, ancestry or ethnicity [5]. In this context, it should be highlighted that mouse geneticists use coat color to identify different strains and transgenic organisms [6]. Another presumable role for hair in mice is protection against frictional stresses [7]. Occasionally, hair also helps in predator-escape by camouflage (eg: artic fox, artic hare and caribou). Thus, hair is of immense significance and in fact, the anxiety of  hair loss in humans has triggered cosmetic businesspersons to make an annual profit of several billion dollars (

Apart from the above-mentioned in situ functions of hair, human kind has put this natural fiber to use in many different ways. Among the plenty of practical applications, quite apparent is the use of animal hairs – wool and fur – in clothing even from the age of Neanderthal. (Braaten, Ann W. (2005). “Wool”. In Steele, Valerie. Encyclopedia of Clothing and Fashion3Thomson Gale. pp. 441–443. ISBN 0-684-31394-4.). Other notable applications are the use of animal hairs in manufacturing felted crafts, blankets, bed, other home furniture, upholstery, brush industry, pet hairs to develop vaccine against allergies, in aesthetic jewellery etc. Both human and animal hair are used as an environmental clean-up agent, especially to clear oil spills due to their great absorbent nature, as compost to enrich the nitrogen content of soil, as a stuffing material for pillows and other insulated threads.

The hair in its details:

The term ‘hair’ not only includes the apparent ‘hair filament’ or ‘hair shaft’ that protrude out of the skin but also the part that lies within the dermis denoted as ‘hair follicle’. The follicle is responsible for regrowth of the hair filament when it breaks, sheds, pulled or plucked-off. A cross-section of the hair shaft has revealed the existence of 3 distinct concentric layers namely medulla, cortex and cuticle [8, 9]. The medulla is the innermost central layer of the hair, while the cuticle is the transparent outer layer made up of scales;  the cortex lies in-between and it contains the melanin pigments (Figure 1) [8, 9]. However, when the hair follicle is sectioned longitudinally, one can observe the existence of 5 additional layers exterior to the hair shaft and within the dermis (Figure 2). These are (i) the Henley’s layer – a thin pale epithelial stratum, (ii) the Huxley’s layer – a thin granular epithelial stratum, (iii) another cuticle (together, these three layers called as the Internal Root Sheath – IRS), (iv) the External Root Sheath (ERS) – an epithelium composed of several cell layers that wraps around the follicle and is contiguous with the epidermis and finally, (v) the connective tissue sheath of the dermis (also known as the dermal root sheath – DRS) that covers the ERS [8, 9].  Inside the follicle, the hair shaft emerges from a bulb-shaped structure called the “hair bulb,” wherein the Henle’s and Huxley’s layer merge and become indistinguishable and so does the IRS and ERS to form an undifferentiated group of cells denoted the “hair matrix” [8, 9]. Melanin pigments and cell mitoses are obvious features of the hair matrix. The connective tissue sheath forms a pear shaped structure called the ‘dermal papilla’ that contains numerous fibroblasts, collagen fibers, and blood capillaries for nourishing the growing and differentiating cells of the attached hair bulb [8, 9]. Two other structures found generally associated with the hair follicle are the ‘arrector pili’ and the ‘sebaceous gland’. Arrector pili is a small, smooth, mesenchyme-derived muscle usually attached to the DRS. The contraction of these muscles in response to cold, fear or other strong emotions causes the hairs to stand on end (piloerection), known colloquially as goose bumps. Notably, arrector pili is poorly developed in hair of the axilla and is absent in hairs of the eyebrows and eyelashes (cilia). Sebaceous gland is a bud like protrusion of the epithelial wall of the hair follicle into the surrounding mesoderm; the central region of the bud degenerate to produce a fat-like substance known as the sebum. (Chapter 21: Integumentary System from Langman’s Medical Embryology Twelfth Edition by T.W. Sadler, 2012, pp. 341).

The evolution of hair

The emergence and evolution of various epidermal appendages, especially hair, has long been a debatable topic owing to several schools of thoughts. Some of these are based on the functions of hair suggesting that it might have originated to fulfill tactile and sensory functions, to protect the skin from different pathogens and to insulate the body from surroundings, as an anchor for holding the vernix caseosa on the skin until birth (Keith L. Moore, chapter 18, Pg.379) etc. A convincing postulate is the gradual evolution of reptilian scales into hairs and feathers [10]. However, lack of evidence in this aspect has driven researchers to explore in different directions and one such group (Dhouailly et al) propose the emergence of hair/feathers to various glands [10]. Recent advancements show that variation in expression of wnt/beta-catenin pathway gives rise to footpads, glands, and hairs or feathers [11-14]. The absence of this signaling pathway corresponds to the corneal epithelium; low levels correspond to the emergence of glands while high levels correlate with the establishment of hairs or feathers. Further, activation of beta-catenin and inhibition of BMP are found to form hair follicles instead of sweat or mammary glands and vice versa [15-17]. Therefore, it is now hypothesized that the synapsid lineage upon separating from the amniotes evolved a glandular integument rather than a scaled one [10]. In line with this, living representatives of the synapsid lineage show a transitional progression among hair and glandular structures, for example, monotremes are found to have mammary glands associated with hair follicles which are observed to be transiently retained in marsupial embryos [18] and finally lost in eutherian embryos. Further, dermatological observations hypothesize the evolution of hair from sebaceous glands [19] wherein the hair shaft serve as capillaries to transport the product of the sebaceous glands to the skin surface thereby mediating insulation and maintenance of water levels. This can be understood in parallel with the emergence of the mammary gland from ancestral sebaceous glands in the present day living monotremes which have associated hairs required to feed its young ones [10].

Finally, in spite of the presence of a well-preserved and enormous fossil evidence, comprehending the evolutionary trajectory of hair has been an extremely tedious job. Several theories are put forward in this regard but all of them have their own critics.

The emergence of hair:

Hair formation begins when a cluster of basal epidermal cells proliferates and extends downward into the dermis as a bud (epidermal placode).  The process of hair bud formation is influenced by mesenchymal fibroblast cells that team up below the placode to form an aggregate known as ‘dermal condensate (DC)’. The epidermal placode continues to grow downward at an oblique angle, forming the “hair germ,” which later gives rise to the early hair peg. Over time, the terminal end of the hair peg assumes a bulbous club-shaped structure that is invaginated by some of the mesenchymal cells in the DC to give rise to the dermal papilla (DP). Also, melanoblasts migrate into the hair bulbs to differentiate into melanocytes. The cells of the DC that do not invaginate the hair bulb form the papillary pad, which remains connected with the DP by a neck that narrows progressively towards the proximity of the pad. The DP gives rise to the blood vessels and nerve endings of the hair follicle while the pad differentiates into the DRS and arrector pili. Meanwhile, the epidermal cells in the centre of the hair peg and directly above the DP produce the matrix cells, which continuously proliferates and differentiates into a cone of spindle-shaped cells that eventually keratinize and is pushed upward to form the hair shaft. The melanin pigment produced by the melanocytes is transferred to the matrix cells several weeks before birth, thus effecting hair colour. The cuboidal shaped peripheral cells of the hair peg give rise to the epithelial hair sheath (IRS and ERS) and to the sebaceous gland. These glands secrete sebum into the hair follicle that finally reaches the skin. In light of the above, the hair follicle can be essentially considered as a product of proliferation and a unique series of differentiation stages of localized keratinocytes [7, 20].

The first hair, known as lanugo hairs, appear by the end of third month on the eyebrows, upper lip and chin and become plentiful by 17-20 weeks; they help to hold the vernix of the skin. At the time of birth, the lanugo is shed and is replaced by coarser hairs arising from new hair follicles.

Genetic signaling behind genesis and formation of hair

Epithelial–mesenchymal interaction and pattern formation are the two distinct crucial processes that underlie folliculogenesis and hair shaft development. Several signaling pathways collaborate amongst one another to achieve this evolutionary novelty and understanding the underlying mechanisms hold the answers for not only hair follicle development/regeneration, but also regeneration of the epidermis, wound healing and even the etiological underpinnings of many epidermal neoplasia [121]. Genetic signaling involving hair follicle morphogenesis can be divided into three significant events, which can be elaborated as follows.

Hair follicle induction and placode formation

Hair follicle formation arises through a complex cross talk occurring between dermal cells and their overlying epithelial cells {Schmidt-Ullrich, 2005 #103}. Experiments in mouse and chicken has established that dermis from hair-bearing regions, if combined with epidermis devoid of hair, would induce skin appendage development characteristic of the region of dermis [122]. This provides evidence for a primary signal emanating from the dermis and such a signal instructs the overlying epithelium to aggregate and form a hair placode. However, molecular nature of such a signaling is highly mutable and several studies have outlined the involvement of Wnt/β-catenin pathway, EDA/EDAR/NF-kB pathway and transcription factors like Msx-1&2 in placode formation and maintenance (Gat et al., 1998; Andl et al., 2002) [123][124][125].

Placode inhibitory signals and patterning

In contrast to placode forming signals, placode inhibiting signals play a vital role to avoid the formation of ectopic placodes or even several skin related tumors. Interaction between placode forming/activators (Wnt 10b, β-catenin, follistatin, Noggin and Gremlin) and inhibiting signals (BMP and Dkk4) lead to the establishment of a regular array of placodes4. Ectopic expression of BMP 2 & 4 is found to suppress feather buds in chick embryos suggesting their role in HF repression and pattern formation [126, 127]. Ectopic expression of the Wnt/b-catenin inhibitor, DKK1, causes blockage of hair follicle induction whereas constitutive activation of Wnt/b-catenin results in stimulation. Also, null- and loss of function- mutations in proteins of the Wnt signalling cascade results in a complete or partial shutdown of HF formation [123] owing to its significance during several different HF stages.

Such a hypothesis was initially proposed by Turing as early as 19525, suggesting the interaction of counteracting morphogens – activators and inhibitors – which interact to generate self-organizing de novo patterns of epidermal appendages. Recently, Sick et al. 2006 utilized both experimental and computational modeling approach to show that WNT and its inhibitor DKK determine the spacing of murine hair follicles (Sick, 2006 #74). Simultaneously, by utilizing a Frizzled6 Knockout mice, Wang et al. demonstrated the existence of two different systems that determine the orientation of a hair follicle depending upon the average orientation of the neighboring hair follicles (Wang, 2006 #75).

Organogenesis and Induction of dermal condensate

Dermal condensation simultaneously parallels placode proliferation and hence both of these events are precisely interdependent in contributing to the development of HF [128]. The condensation/maturation of dermal fibroblasts depends upon signals emanating from the overlying placodal cells. PDGF-A released by the placodal cells communicate with its receptor PDGFR present in the underlying dermal fibroblast cells thereby mediating dermal condensation [129]. The absence of PDGF-A leads to the formation of a small dermal papillae, thin hair and dermal sheath abnormalities in mice, indicating their significance in dermal condensation and maintenance [129]. Another significant signaling pathway mediating cross talk between placodal cells and dermal fibroblast cells is FGF signalling [130]. Fgf20 and Shh expressed in hair placodes [121, 139] is induced by epithelial Wnt/ β-catenin & EDA/EDAR/NF- kB signalling [140]. Fgf20 interacts with its receptor Fgfr1 expressed in the upper dermal cells to mediate dermal condensation [131] while  Shh activates the expression of cyclin D1 which contribute to epithelial placode proliferation and it’s down growth [136-138]. Epithelial Shh induction further drives DP maturation via regulation of dermal Noggin. Activation of Noggin via Shh involves a complex epithelial mesenchymal cross-talk which includes epithelial laminin 511 and mesenchymal dermal β-integrin interaction resulting in the formation of primary cilia which in turn induces epithelial Shh to activate its downstream effector proteins like Ptc, smo and gli. Shh signaling in combination with PDGF signaling activates dermal noggin secretion, thereby inhibiting dermal BMP and hence DP maturation [141].

Sonic hedgehog is a central key player which mediates epithelial follicle down growth and maturation of dermal condensate15,16,17.

Organogenesis and Induction of dermal condensate

These simultaneous processes (placode proliferation to form the epidermal follicle, and maturation of dermal condensate to form the dermal papilla) give rise to mature HF which additionally requires the antagonistic action of BMP as well [128].

Signaling molecules like Noggin, follistatin, and gremlin mediate BMP inhibition and further contribute to HF formation [26, 132-135]. Sonic hedgehog is a central key player which mediates epithelial follicle down growth and maturation of dermal condensate.


Succeeding HF formation, its differentiation is closely regulated by Notch, Wnt and Bmp signaling pathways. The immature HF differentiates into at least 7 different epithelial cell layers giving rise to the mature HF [142]. Notch, a membrane-bound signaling protein with its ligand serrate 1 & 2 regulates differentiation mainly in the epidermis [143], its effector proteins like Wnt5a & FoxN1 regulate HF keratinocyte differentiation & signal specific pigment transfer from melanocytes to keratinocytes of the mature hair cortex [144].

DP directly regulates differentiation of hair shaft progenitor cells through facilitating expression of Sox2. Sox2 modulates hair growth by regulating HF progenitor cell migration. This is achieved by upregulating BMP6 (inhibitor of cell migration) and upregulating Sostdc1 (inhibitor of Bmp) [143]. Bmp with its receptor BMPIA is further implicated in epithelial stem cell maintenance, hair shaft progenitor differentiation, and DP cell maintenance. This is achieved by activation of GATA3 which in turn regulates Bmp levels [145]. Further, several studies have identified transcription factors like Msx2, FoxN1 and Hoxc13 and BMP signaling to regulate hair shaft differentiation [146-151] while transcription factors like Gata3 and Cut1 in regulating IRS differentiation [152-154].

Hair follicles are found in regularly spaced arrays, with large primary hair follicles being interspersed by smaller follicles throughout the skin. In addition, there exists a marked difference in length, texture, and growth of the hair in different regions of the body (scalp, axilla etc.). Pattern formation is responsible for this regular pattern and the anterior-posterior orientation of hair follicles, but the mechanisms that underlie the generation of such patterns remain poorly understood in humans. However, epidermal appendage patterning is more pronounced in animals where it determines the dorsoventral patterning, cranial hair patterning, formation of vibrissae and tail hairs and therefore much work in mouse models has provided accountable information on this process  [21]. Turing, in 1952 [22], suggested a model (Reaction-Diffusion model; in short, RD model) that involved two different types of morphogens – activators and inhibitors – which interact to generate self-organizing de novo patterns of epidermal appendages. Since then, a number of studies have attempted to simplify/extend Turing’s RD model to explain the patterning of hair follicles in regular arrays wherein activators determine the size of the follicle domain, while inhibitors define follicle spacing [23-25].   Molecular developmental studies have shown that Fgf4, follistatin, noggin, and Shh areactivators of follicle development, while BMPs are follicle inhibitors [26-28]. The follicle inhibitors have greater diffusion capabilities and are active in the interfollicular space where they suppress follicle development while the locally acting follicle activators counteract the inhibitory signal giving rise to hair follicle morphogenesis. More recently, Sick et al. 2006 utilized both experimental and computational modeling approach to show that WNT and its inhibitor DKK determine the spacing of murine hair follicles thus strongly supporting the RD mechanism [29]. Simultaneously, by utilizing a Frizzled6 knockout mice, Wang et al. demonstrated the existence of two different systems that determine the orientation of a hair follicle depending on the average orientation of the neighbouring hair follicles: a global orientating system that acts early in development and is Fz6-dependent, and a local orienting system that is Fz6-independent and acts later. Further, this study showed the importance of planar cell polarity signaling in directing the orientation of hair follicle [30]. Thus, a well-timed interaction among various different cell signaling pathways results in the formation of properly oriented and spaced hairs.

Types of Hair in Mice and Men

The basic structure of skin and associated epidermal appendages is generally similar in both mice and men, with some regional exceptions and differences in size, the density of hair follicles, distribution etc (Table ???). At the outset, the mouse has pelage (hair coat) and a tail, unlike humans. The mouse pelage is composed of four distinct types of hairs namely, guard-, awl-, auschene- and zigzag hairs that differ in their length and morphology.  The mouse-tail epidermis is thicker and has relatively sparse hair follicles compared to the pelage, while the muzzle skin has specialized hairs known as ‘vibrissae’, which serves as a somatosensory organ. Perianal hairs and specialized sebaceous glands are also found in the mouse genital region. In humans, two types of body hairs can be seen, viz a viz, the fine ‘vellus’ and thick ‘terminal’ hairs. Humans lack vibrissae, but males do possess whiskers, a form of terminal hair on the face. Like human palms and soles, the mouse footpads are devoid of hair and in both cases, the epidermis is markedly thickened. However, mice have relatively smooth plantar and palmar surfaces on their footpads in contrast to the fingerprints of humans (rete ridges and pegs exacerbated in the palms, soles, and digits). The human axilla contains both apocrine and eccrine sweat glands; mice has eccrine sweat glands exclusively present in the pads of their paws, and its trunk skin lacks sweat glands altogether.

Hair type Mouse Human
Body Guard






Other Cilia (eyelashes)

Facial/muzzle (vibrissae)


Distal limbs (vibrissae)



Cilia (eyelashes)


Facial (beard, mustache)



Emergence of hair 5 days postpartum 19–21 weeks of gestation
Hair cycle Wave pattern with zones in adults Mosaic pattern
Tail and tail hairs Yes No


Journey of the hair follicle: Hair cycle

After initial embryonic morphogenesis, the hair follicle undergoes a regular cycle of events that are distinguished into four different phases: (i) anagen – phase of growth, (ii) catagen – regression phase, (iii) telogen – resting phase, and (iv) exogen – shedding of hair follicles [31-34] (Dry, 1926; Kligman, 1959). The exogen phase is also referred to as the late telogen or early anagen. Division of hair cycle into different phases is governed by certain histological characteristics as elaborated in detail by Muller-Rover in 2001 [31]. Progression through these phases can be monitored by studying the expression of molecular markers specific to different stages of the hair growth cycle. Again, a variety of scoring systems have been developed to further subdivide anagen and catagen, with some subparts in both mice and humans (Table ???). Cycling of the hair follicles in human scalp is quite different from that of the mouse pelage: humans exhibit a wavelike growth pattern in utero  that changes to a mosaic growth pattern, whereas mice have a wavelike pattern at birth  which later switches to more of a regional cycling domain pattern when the mice ages.

Table ??? Phases of the Mouse Hair Cycle

Anagen Catagen Telogen Exogen
I I One stagea Not defined anatomically
IIIa,b,c III
V     V
VI     VI
aAlthough more complicated based on hypodermal fat thickness.


The first and the foremost phase, anagen, is the active phase of growth of the hair follicle including its morphogenesis and is the longest phase of hair cycle in a healthy individual. This phase restarts once again after the hair follicle completes its resting phase. Hair follicle xenografting experiments have not only revealed six morphologically different anagen sub-stages but also a platform to understand telogen-anagen transition, since the uninterrupted and dynamic nature of these sub-stages makes it difficult to study them in situ [35]. Anagen I is found to have a triangular or a crescent shaped secondary hair germ (SHG) with a small rounded dermal papilla which may contain some melanin clumps and a sprawling connective sheath  [35]. In anagen II, the SHG undergoes proliferation driven thickening and elongation which partially wraps around the DP that still resembles the preceding anagen stage. The SHG then gives rise to the hair matrix, which further differentiates into the hair shaft. Hence the presence of localized clusters of proliferating cells and absence of apoptotic cells are considered as markers of this stage [35]. With the onset of anagen III, hair matrix develops into a 4-5 cell layer thick body wrapping around an enlarged and oval shaped DP. It is at this stage the hair shaft becomes completely visible. Anagen III is again subdivided into anagen IIIa, IIIb, and IIIc based on the successive appearance of cortex at anagen stage IIIb and medulla at stage IIIc. Further, hair follicle melanogenesis is observed to begin at anagen IIIc [36]. In the succeeding stage, anagen IV, a fully mature hair shaft with proper medulla, cortex and cuticle is easily observed (through H&E staining) with its tip reaching the sebaceous gland and hair pigmentation is re-initiated. A significant down growth of the HF is observed through the presence of a distinct connective sheath identified at the proximal end of the hair bulb. Among the final stages of hair follicle maturation anagen V – VI, the DP becomes onion like and hair pigmentation cells in the hair matrix reaches the Auber’s line. Finally, the hair shaft emerges above the skin and is visible.

(late telogen is much like Anagen I as it has a crescent-shaped secondary hair germ; late catagen also contains a sprawling connective sheath as like Anagen I)

At the conclusion of the anagen stage, the lower portion of the follicle undergoes catagen, a carefully orchestrated destruction by apoptosis [37]. Catagen itself can be subdivided into three stages i.e. early-, mid- and late- catagen [38]. In Early catagen (corresponding to murine catagen 1-4)1, the DP undergoes a reduction in volume as it condenses to form an almond shape body which is enclosed by a thin sheath of hair matrix cells [35]. At this stage, melanogenesis terminates giving rise to a characteristic less pigmentation at the proximal end of the hair shaft as compared to rest of the hair cycle stages [36, 39, 40]. Finally, the bulge region and the hair shaft remain morphologically constant as compared to Anagen VI [35]. The volume of the hair matrix and DP decreases further as early catagen transits to mid catagen (Corresponding to murine catagen 5-6)1. At this juncture, a 1-2 layers’ thick hair matrix is easily observable. Further, a club hair with brushy ends become prominent and is often found to be located above the dermal/adipose boundary. In addition to the club hair, a newly forming epithelial strand (future hair shaft) can easily be identified. This newly formed strand lacks pigmentation and often has a ruffled morphology. The vitreous membrane of the connective sheath grows thicker as compared to early catagen. Finally, apoptosis in the regressing epithelium can easily be visualized through apoptotic specific assays [35]. The last stage of catagen i.e. late catagen (corresponding to murine catagen 7-8)1 involves a characteristic loss of the hair matrix cells with further condensation of DP finally resulting into a ball shaped body. The club hair is more prominently visible as compared to earlier catagen stages and the epidermal strand has shortened significantly as compared to mid catagen. Further, apoptotic cells can be seen in the epidermal strand as well as the shrinking sebaceous gland [35].

Catagen phase is followed by the Telogen,wherein the hair follicle is placed above the dermal/adipose boundary. The resulting telogen hair is quiescent in terms of cell cycle. The DP contracts to form a well-rounded compact body which is separated by the unpigmented club hair through a shortened epithelial strand known as the ‘Secondary hair germ’ (future hair shaft) [35]. At this stage the epidermal layer or the sebaceous glands lack apoptotic cells but, previous reports suggest the presence of a few dispersed proliferating cells in the SHG and in distal epithelium [32]. Finally, in most cases, the telogen is followed by the shedding of the hair in exogen [41]. This gives rise to Kenogen, a late telogenic phase without a club hair, which might last for several months in humans [42].

This Anagen stage is reinitiated when the epithelial stem cells of the hair bulge respond to signals from the activated dermal papilla (Ito, 1986, 1989).

Abnormalities in the hair growth cycle lead to several hair defects, which makes it a significant area of research. Even a mild decrease in anagen to telogen ratio can result in a stark increase in the amount of hair fall. Therefore, studying individual hair cycle stages may illuminate the biology of hair and finally help us to conquer hair loss.

Abnormalities of hair:

Hair can be used to express cultural, sexual, and religious individuality and therefore disorders of hair growth may affect self-esteem, social functioning, and quality of life of an individual. Hair loss is caused by a range of factors such as passive lifestyle, poor diet low in protein or iron, fluctuation in hormonal levels, genetic composition of the individual, etc. Further, hairloss may occur either due to medical disorders, such as a hyperactive or underactive thyroid gland, diabetes, secondary syphilis, anemia, systemic lupus erythematosus, severe infections, certain tumors, or as an effect of medications for gout, arthritis, high blood pressure, depression, high doses of vitamin A, chemotherapeutic drugs and even oral contraceptives that influences hormonal levels. Thus, deviations of hair growth may also be a manifestation of internal disease and thereby a vital diagnostic clue for all clinicians. Physical factors that contribute to hair loss includes constant pulling/traction of hair (traction alopecia), excess bleaching, dyeing, over-teasing or excessive straightening with hot iron, use of metal combs etc. Constantly wearing snug-fitting wigs or hats may lead to friction alopecia.

Any structural and molecular abnormalities either inherited or acquired leads to hair loss and many such abnormalities have been characterized in humans as well as in animals. Numerical abnormalities have also been documented including hypotrichosis and hypertrichosis (reduction or increase in hair density, respectively). Depending upon these causes’ hair loss disorders have been classified into several domains, the common classification being ‘cicatricial’ and ‘non-cicatritial alopecia’ based on the presence and absence of scarring, respectively.  Non-scarring forms include (i) Androgenic alopecia, (ii) Alopecia areata, (iii) Alopecia Universalis, (iv) Alopecia totalis (v) Trichotillomania, (vi) Telogen effluvium, (vii) Anagen effluvium. Scarring forms can be further sub classified into primary form if the hair follicle is the target of destruction and secondary form if the hair follicle is just is an innocent bystander, destroyed by another cause (Figure ???). The destroyed hair follicle is replaced by fibrotic tissue. Scarring forms include conditions caused by growth disorders/inherited diseases (epidermal nevi-darier disease), damages from natural causes (mechanical trauma-burns), infections (microbial or viral), neoplasia and various other skin diseases of unknown etiology.

Hair disorders peculiar to blacks, such as traction alopecia and folliculitis (caused by braided hairstyles), ingrown beard hair (pseudofolliculitis barbae) and acne keloid (folliculitis keloidalis) (Disorders of Hair Growth: Diagnosis and Treatment
Second edition. Edited by Elise A. Olsen. 544 pp., illustrated. New York, McGraw-Hill, 2003. $195. ISBN: 0-07-136494-3)

Androgenic Alopecia

Androgenic alopecia or male pattern baldness is a common form of hair loss affecting both men and women, with onset generally at the age of 12-15 (i.e., with puberty) [43]. The extent of hair loss is different in both the sexes: males start losing hair at the temples and the crown followed by partial or complete baldness; women start to have thinner hair all over the scalp with pronounced hair fall, and do not develop complete baldness as is frequently observed in men. . Androgenic alopecia is a polygenic trait and can be inherited from either of the parents [44, 45]. The phenotype is a result of shortening of the anagen phase and simultaneous thinning of the hair follicle [46], which is thought to be androgen dependent [47]. Increased 5α-reductase activity leads to peripheral conversion of testosterone to dihydrotestosterone (DHT) in affected individuals and elevated DHT binds to the androgen receptor with a greater vigor consequently resulting in the activation of genes that restrict the anagen phase and thinning of the hair follicles [48-51]. Several other medical conditions viz. prostate cancer, coronary heart diseases, obesity, diabetes, hypertension, etc., are also found to be associated with androgenic alopecia..

Alopecia Areata

Alopecia areata is a T-cell associated autoimmune disorder of the nonscarring type, with circular or oval patterns (patches) of hair loss and hairs at the periphery of the affected area resemble ‘exclamation mark’. This denotes a damaged hair with an absent distant end i.e., the thicker end, which becomes thinner as it enters the scalp [52, 53].  The condition is reversible in 50% – 80% of subjects of a particular subgroup and nail ambiguities might co-occur in 7% – 66% of the individuals [54, 55]. If the disappearance of the hair is in a snake-like manner, it is known as Ophiasis, while complete loss of scalp hair is termed Alopecia Totalis [56, 57]. In subjects where there is a global hair loss, it is denoted as Alopecia Universalis [56, 58]. Anomalous shortening of the anagen phase and elongation of the telogen phase has been identified as the underlying cause for hair fall [52, 53, 59, 60]. Studies suggest the involvement of several genes is Alopecia areata  [61] and the condition co-occurs with several autoimmune diseases including Type I diabetes, rheumatoid arthritis, thyroid dysfunction, vitiligo and lupus erythematosus [62-65].


Trichotillomania often referred commonly as ‘hair pulling disorder – HPD’, is a psychiatric disorder in which individuals develop a staunch habit of pulling one’s own hair due to anxiety, boredom or other negative emotions. Eyebrows, eyelashes, and scalp are the common pulling sites [66]. It is estimated that about 1% of the general adult population meet the criteria for HPD [67]. Such a disorder is more commonly reported in children with females occupying a larger subset of the reported cases [68].

Telogen effluvium

Telogen effluvium (TE) is a diffuse form of hair disorder involving improper hair growth cycle, which might be a result of several stress-related disorders or can be drug induced. Telogen effluvium, as the name suggests, is the result of the increased shedding of club hairs in the Telogen phase preceded by premature termination of the anagen phase [69-71].  Telogen effluvium affects both sexes, but women are over-represented probably because of hormonal changes in the postpartum period and greater anxiety. Further,  it has been observed that only women fall prey to chronic Telogen effluvium and the condition worsens as the age progresses [72]. In a normal individual approximately 86% of the hairs are in anagen, 1% in catagen and the rest 13% in telogen while for a TE patient the distributions change – 70% of anagen and 30% of telogen (cite 16 & 17 from telogen effluvium).

Anagen effluvium

In anagen phase, hairs are actively involved in mitotic divisions and higher metabolic activities and any impairment in such processes affects the proliferating cells leading to shedding of the hairs (cite 1 from anagen effluvium). However, the dormant stem cells are left unharmed and therefore hair loss is usually reversible. Chemotherapeutic drugs like alkylating agents, mitotic inhibitors, antimetabolites or radiotherapy in the head and surrounding areas, exposure to several toxic chemicals [73, 74],  systemic diseases like peribulbar inflammation, systemic lupus erythematosus, secondary syphilis and conditions like alopecia areata [75], pemphigus vulgaris [76] can lead to Anagen effluvium. If anticancer drugs cause the condition, it is known by the name of ‘Dystrophic anagen effluvium’ (DAE). The other type termed ‘loose anagen hair syndrome’ (LAHS) is an autosomal dominant disorder with incomplete penetrance, and arises either due to loosely anchored anagen hairs or improper keratinization of the inner root sheath that renders the hair easily pluckable [77]. LAHS primarily affects light haired children, predominantly females [78-80].

What about cicatritial alopecias???

Genetic basis of hair loss

In the past 10 years, there have been specific genes assigned to many of the disorders with abnormal hair. Abnormality in hair growth, structure and distribution is observed in a host of genetic conditions and such abnormalities can manifest either in isolation or as part of a range of clinical features. Online Mendelian Inheritance in Animals ‘OMIA” ( lists about ~ 800 genes which have been implicated in the hair loss phenotype, whether as a major phenotype or an associated phenotype with other defects.

Hair abnormalities as part of ectodermal dysplasia syndromes. There are many case reports and reports of pedigrees with structural hair abnormalities and other dysmorphic and developmental abnormalities that are far too numerous to discuss individually. In many families, there are different structural alterations in hairs from the same individual and between affected family members.

Hypertrichosis(Excessive hairiness) is caused by an unusual abundance of hair follicles. It may be localized to certain areas of the body, especially the lower lumbar region covering the spina bifida occulta defect or may cover the entire body. Atrichia, the congenital absence of hair, is usually associated with abnormalities of other ectodermal derivatives, such as teeth and nail (Chapter 21: Integumentary System from Langman’s Medical Embryology Twelfth Edition by T.W. Sadler, 2012, pp. 342).


Hypotrichosis is a disease where there is an absenteeism of hair growth as opposed to alopecia where there is a successive hair loss. The absence of hair or hypotrichosis is observed independently in several diseases and in combination with a number of other diseases mostly giving rise to ectodermal dysplasia. Some of these diseases include Hypotrichosis simplex, Marie Unna Hypotrichosis, Hypotrichosis Congenita, Clouston hydroitic ectodermal dysplasia etc.  All these diseases are found to influence several genes including, APCDD1, CDSN, keratin family, RPL21, SNRPE, Hairless, GJB6, LIPH, LPAR6 etc.

Ectodermal dysplasia

Ectodermal Dysplasias (ED) are a heterogeneous group of rare heritable conditions, which affect the development, and structure of ectoderm-derived organs such as the skin, hair, sebaceous glands, mammary glands, teeth, and nails. Each syndrome in this group is usually characterized by different combination of symptoms, with the extent ranging from mild to  severe. Currently, more than 150 distinct diseases are grouped under ED and based on the ectodermal appendage that is affected, these disorders are broadly classified into four groups: Trichodysplasia (hair dysplasia), Dental dysplasia, Onychodysplasia (nail dysplasia), and Dyshidrosis (sweat gland dysplasia). Again, subclassifications exist considering the different permutations and combinations of the involved defective ectodermal appendage. The most common form is the X-linked hypohidrotic form (HED) also known as ectodermal dysplasia 1, manifesting three cardinal symptoms: sparseness of scalp and body hair (hypotrichosis), inability or reduced ability to sweat (anhidrosis or hypohidrosis), and abnormal or missing teeth (anodontia or hypodontia){Trzeciak, 2016 #195}. EDA is observed to be the most frequently mutated gene in HED {Cluzeau, 2011 #194}. Apart from HED, the three recognized EDs that show features from all four of the primary ectodermal dysplasia defects are:

  • Ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC)
  • Rapp-Hodgkin HED
  • Ankyloblepharon, ectodermal defects, cleft lip/palate (AEC) or Hay-Wells syndrome.

where malfunction in the integument is a common observable trait. Several genes influencing ED have been identified with the numbers increasing at an alarming rate. Some of the commonest ED’s include

Ectodermal Dysplasia with mutations in TP63 gene

TP63 gene encodes a transcription factor which is involved in epidermal synthesis of several organs including skin. Mutations in this gene have been observed to cause certain ectodermal defects including Hay-wells syndrome, Rapp-Hodgkin syndrome and Ectrodactyly ectodermal dysplasia. Among most of the disorders affecting TP63, affected individuals are observed to exhibit hypotrichosis with pilli torti, hypodontia, nail dystrophy, cleft lip/palate and certain cases with limb anomalies (EEC).

Ectodermal Dysplasia with mutations in EDA/EDAR pathway

EDA pathway includes three main genes coding for TNF-alpha family members: EDA – a ligand, EDAR – a receptor and EDARADD – an adaptor. These genes contribute towards the development of several ectoderm-derived organs, including hair, feathers, teeth, and mammary glands. Mutations in this particular pathway have been observed to cause hypohidrotic/anhidrotic ectodermal dysplasia. Upon observing human patients it has been found that affected individuals are observed to exhibit hypotrichosis, hypodontia, and hyperhidrosis, anomalies of the eye & mucous membranes and palmoplantar hyperkeratosis.


Monilethrix is a hair disorder characterized by hair shaft anomalies with perifollicular papules and erythema (Shimomura, 2016). This anomaly is popularly known as the beaded hair where hair shafts resemble beads with varying diameter. It arises through heterozygous mutations in type II hair keratin genes, including KRT 81, 83 and 86 (Winter et al., 1997)(van Steensel, Steijlen, Bladergroen, Vermeer, & van Geel, 2005).


S.No. Gene Disease or symptoms Clinical features of disease Gene product Mode of inheritance
1 NF-kappa BIA Anhidrotic ED with immune deficit Recurrent infections, T-cell deficiency, dry and rough skin, sparse hair Member of NF-KB inhibitor complex Autosomal dominant
2 ERCC3 (Excision-repair cross complementing rodent repair deficiency) Trichothiodystrophy

Xeroderma pigmentosum

Sun sensitivity, risk of malignancy, brittle hair & nails, growth retardation, learning deficit, pigmentation abnormalities. Helicase subunit of TF2H. Autosomal recessive
3 MAP2K1 Cardio-facio-cutaneous syndrome Heart defects, distinctive face, intellectual deficit, ectodermal defects, sparse hair, skin lesions. MAP kinase Autosomal dominant
4 KRT 74

KRT 85

Hox C13

Pure hair and nail ectodermal dysplasia


Brittle hair, hypotrichosis, onychodystrophy, micronychia. Keratin gene cluster Autosomal recessive
4 Tp63 Ectrodactyly ectodermal dysplasia


Limb deformities, skin defects, cranio-facial clefting, ectodermal deficits, anomaly of hands and feet. DNA binding domain of TP53 related TFs. Autosomal dominant
5 Ectodysplasin (EDA)



Hypohidrotic ED


X-linked HED

Disruption of appendage development

Delay in healing

TNF superfamily X-linked

Autosomal dominant


Autosomal recessive

6 GJB6 Clouston syndrome Hypotrichosis, nail dystrophy & occasional palmoplantar keratoderma Autosomal dominant
7 PORCN Focal Dermal Hypoplasia


Defects in skin, skeleton & ectodermal appendages. X-linked
8 DLX3 Tricho-dento-osseous syndrome Defects in hair, teeth and bone. TF Autosomal dominant
9 PVRL4 ED-Syndactyly Syndrome


Alopecia, Widely spaced teeth. Codes Nectin4

(Cell adhesion molecule)

10 FOX I3 Canine ED Abnormally shaped teeth, scanty hair. Autosomal semi-dominant
11 Pericentric inverted chromosome 9 (Human) Hypohidrotic ED Absence of sweat glands, Hypotrichosis, Hypodontia, intolerance to heat, facial abnormalities. X-linked
12 DL

(Downless gene)

13 RECQL4 Rothmund-Thomson Syndrome


Disordered epidermal appendage, skeletal anomalies, Cataract, premature aging, Predisposition to neoplasia, Chromosomal instability, increased clonal rearrangements. Helicase

Maintenance of genomic and chromosomal integrity.

Autosomal recessive
14 TRPS1 Tricho-rhino-phalangeal Syndrome type 1 Sparse scalp hair, pear shaped nose, small teeth with dental malocclusion, thin nails, conical shaped epiphysis, short stature & skeletal malformations. GATA binding transcription factor Loss of function mutation
15 DKC1 Severe changes in skin and epidermal appendages X-linked
16 Cathepsin C


Papillan-lefevre syndrome Palmoplantar hyperkeratosis, Hypotrichosis, nail fragility and periodontis. Lysosomal protease

Activating serine protease

Autosomal recessive



S.No. Gene Mode of inheritance Symptoms Location and mutation
1 Angora (Go) Autosomal recessive Abnormally long truncal hair

Prolongation of anagen phase for about 3 days

Scattered hair follicles

Defective hair shaft

Murine chromosome 5

Deletion in Fgf5 gene.

2 Asebia mouse (SCD1 deletion) Autosomal recessive Alopecia

Lack sebaceous glands

Minimal or absence of sebum production

Epidermal hyperplasia

Chromosome 19
3 PORCN X-linked dominant Defects in skin, skeleton & ectodermal appendages.

Eye & ear abnormalities

Brittle and sparse hair


Supernumerary nipples


Murine X chromosome
4 P63 Autosomal dominant Devoid of epithelial appendages like mammary, salivary and lachrymal glands, hair and teeth. Murine chromosome 16
5 Tabby X – linked

Autosomal dominant


Autosomal recessive

Absence of primary hair follicles

Secondary hair follicles form but growth is shunted.

Disruption of appendage development.

Murine X chromosome
6 Downless1



Autosomal dominant Defects in hair follicles, tooth, sweat gland, preputial gland, meibomian gland, and tail development.

Analogous to human HED

Murine chromosome 10
7 TRAF6 Focal alopecia behind the ears

Alopecia in the tail

Absence of guard hair follicles

Lack of sweat glands

Impairments in sebaceous glands like meibomian, preputial and anal glands.

Murine chromosome 2
8 HOXC13 Absence of pelagic hair, peri-anal hair, cilia and vibrissae.

Deficient filiform papillae of the tongue

Murine chromosome 15
9 Lgr4 Sparse head hair

Focal alopecia behind ears

Abnormal teeth

Reduced hair placodes

Abnormal development of kidney, eyelid, and epididymis

Embryonic/neonatal lethality

Murine chromosome 2
10 Crinkled


Autosomal recessive Reduction in size and number of teeth

Absence of coat hair

Nail dystrophy

Murine chromosome 13
11 Sleek Autosomal dominant Defective hair and teeth

Deformed ectodermal appendixes.

12 Spink5

Netherton syndrome

Autosomal recessive Skin inflammation & desquamation

Hair shaft defects

Severe dehydration

Stunted growth

Murine chromosome 18
13 Zdhhc132

Palmitoyl transferase

Autosomal recessive

(a Luc mutation causes AR phenotype)


Abnormal hair cycle

Epidermal and sebaceous gland hyperplasia


Increased epidermal thickness

Murine chromosome 7
14 Gsdma3 3

(Rim3 mutation)

Autosomal dominant Hyperkeratosis

Abnormal anagen phase at the first hair cycle

Hyperplasia of the epidermal cells of the upper hair follicles

Hyperproliferation and misdifferentiation of the upper follicular epidermis

Murine chromosome 11
15 Gsdma3

(Rco2 mutation)

bare skin (Bsk)


Defolliculated (Dfl)

Autosomal dominant Increase in dermal fibrous tissue

Increasing loss of hair with age

Increased dermal fibrous tissue

Murine chromosome 11
16 Dsg3 Autosomal recessive Suprabasilar blisters on tongue

Skin erosions and eye lesions

Hair loss

Nipple erosions in nursing mothers

Snout erosions and conjunctivitis.

Murine chromosome 18
17 Hairless (Hr) Autosomal recessive Irreversible hair loss,

Wrinkled skin,

Long and curved nails,

Decreasing vibrissae with age

Murine chromosome 14
18 Rhino

(Hair less)

Autosomal recessive Alopecia

Popular atrichia

Inner ear defects

Alterations in neuronal morphology

Intrafollicular apoptosis

Murine chromosome 14
19 St14


Autosomal recessive Compromised epidermal barrier

Epidermal acanthosis4


Ichthyotic skin

Irregular keratinization

Murine chromosome 9
20 Spint1


Severe growth retardation

Hyperkeratosis of the forestomach

Hyperkeratosis and acanthosis of the epidermis

Hypotrichosis associated with abnormal cuticle development

Ichthyosis of skin

Murine chromosome 2

Mitochondria and Hair disorders:

Mitochondria are vital regulators of skin physiology and by producing reactive oxygen species (ROS), they promote epidermal differentiation and hair follicle development [81-83](13). Moreover, mitochondria also play a role in melanocyte function and pigmentation [84]. In a study, skin manifestations such as hair abnormalities, rashes and pigmentation abnormalities, hypertrichosis and acrocyanosis were associated in 10% of the patients with primary mitochondrial disorders. Hypertrichosis is seen in up to 34% of Leigh syndrome patients with mutations in SURF1, a nuclear encoded gene involved in the assembly of mitochondrial complex IV [85, 86]. Several lines of evidence, both direct and indirect, links the MAPK pathway to OXPHOS and thus various syndromes of the MAPK pathway including Noonan, cardio–facio–cutaneous, LEOPARD and Costello syndromes is thought to have a strong mitochondrial component. For example, SHP2 – the downstream regulator of ERK/MAPK – was reported to localize to the mitochondrial intercristae/intermembrane space and approximately half of the patients with Noonan carry a gain of-function SHP2 mutation [87]. RMRP, an endonuclease that cleaves RNAs synthesized from the mtDNA origin of replication to produce RNA primers for leading strand synthesis, is found mutated in Cartilage Hair Hypoplasia (CHH) [88-90]. APLCC (aplasia cutis congenita, reticulolinear, with microcephaly, facial dysmorphism and other congenital anomalies) is caused by mutations in the nuclear COX7B that is indispensable for complex IV assembly and activity, and mitochondrial respiration [91]. Bjornstad syndrome, is caused by mutations in the BCS1L and defective BCS1L leads to fragmentation of the mitochondrial network [92, 93]. Multiple carboxylase deficiency, characterized by skin rashes and alopecia, is caused by mutations in the biotinidase and holocarboxylate synthetase genes [94, 95]. Because one biotinidase isoform is localized inside mitochondria, this disease affects the mitochondrial biotin-dependent carboxylases (BDC), including pyruvate carboxylase [94], and biotinidase deficiency leads to severe ATP depletion [96].The mitochondrial enzymes such as superoxide dismutase and cytochrome c oxidase are affected in Menkes dieases, a fatal X-linked disorder characterized by a widespread defect in intracellular copper transport [97, 98]. In Hutchinson–Gilford progeria syndrome (HGPS), down-regulation of OXPHOS, especially the ATPase complex, accompanied by mitochondrial dysfunction was reported while glycolytic enzymes were up-regulated. Cytochrome c expression was diminished, and complex IV activity was significantly reduced [99]. Mutations in RECQL4, a mitochondria-localized helicase, leads to Rothmund-Thomson syndrome [100, 101], while mutations in RECQL2 observed in Werner syndrome increases mitochondrial ROS production and HIF-1 stabilization [102]. Despite these evidences, the substantial contribution of mitochondria to the pathophysiology and progression of hair loss and associated disorders needs further research. A recent study indicates the direct role of mitochondria in the differentiation of hair follicle stem cell (HFSCs) and dysfunction of mitochondrial respiration delays hair regeneration upon injury [103]. For the numbered references see this paper: (Mitochondrial dysfunction: a neglected component of skin diseases. Rene G. Feichtinger1, Wolfgang Sperl2, Johann W. Bauer3 and Barbara Kofler1).

Epigenetics and hair loss disorders:

During different developmental and post-developmental stages, peripheral tissues are more often than not under a constant insult, undergoing spontaneous degradation and regeneration [104]. These insults usually arise from various environmental interactions affecting a particular genotype, in a unique manner, thereby resulting into differential susceptibility of age-related disorders [105]. Regeneration mechanisms via terminal differentiation among several epidermal stem cells play a vital role in the maintenance of epidermal homeostasis.

Regeneration of epidermal appendages, particularly hair follicles are governed by different cellular signaling pathways that are spatio-temporally coordinated by various epigenetic mechanisms. Epigenetic factors incorporate both activation and repression of several key regulatory elements involved with stem cell regeneration. These elements include transcription factors, (p63, Klf4, AP-1 etc. can add more) cellular signaling pathways, (wnt, Hedgehog, Notch, Bmp etc.) and epigenetic regulators (DNA/Histone modifying enzymes, chromatin remodelers, polycomb genes and Noncoding RNAs) [106-108]. Hair follicles stem cells have developed recent interests in understanding these regulatory elements including several epigenetic mechanisms.

DNA methyltransferase DNMT1, Histone deacetylases HDAC1/2 and polycomb protein groups Bmi1 & Ezh1/2 stimulate proliferation of keratinocyte progenitor cells by repression of cell cycle inhibitors and premature activation of terminal differentiation associated genes [106-108]. Recent reports outline the indispensable role of p63 in chromatin remodeling of EDC locus (include genes governing epidermal barrier [109]) via the genome organizer Satb1 and ATP dependent chromatin remodeler Brg1[110, 111]. Satb1 has a unique role in chromatin organization and refolding via recruiting chromatin remodelers and transcription factors to the concerned loci [112]. Ablation of both Ezh1 and Ezh2 abolishes a crucial methylation mark H3K27me3 which is involved with hair follicle formation and maintenance [113]. Recent developments have yielded the understanding of epigenetic regulatory mechanisms in diseases like Alopecia Areata [114]. These findings outline the involvement of a global increase in DNA methylation levels among patients as opposed to healthy controls [114]. Increased expression was found for DNA modifying factors like DNMT1, MBD1/4, HDAC1, SET7/9, JMJD2C (KDM4C) and JARID1A (KDM5A) and a reduced expression was found for factors including HDAC2/7, JMJD2A (KDM4A), LSD1 (KDM1A) and JMJD2B (KDM4B)[114]. Such epigenetic mechanisms and their cross-talk with cell signaling pathways outline a dearth of clinical intervention strategies which necessitates its significance in understanding different skin related pathologies.

MicroRNAs in hair loss

Rui et al. (2006), cloned more than 100 miRNAs from the skin and showed that epidermis and hair follicles differentially express discrete miRNA families: miR-200a, miR-141, and miR-429 were abundant in the epidermis and scored absent in hair follicles. Another set of 15 miRNAs had elevated counts in the epidermis than hair follicle. When the gene encoding the cytoplasmic miRNA processing enzyme Dicer1 was conditionally targeted in mouse embryonic skin progenitor cells, the resulting embryos survived to term and appeared normal. However, they began to lose weight within 1-2 days after birth, appeared dehydrated and did not survive past postnatal day (P) 4-6.  Histological examination of their backskins shortly after birth, showed that the hair germs evaginated into the epidermis distorting it by forming cyst-like structures that became prevalent with age (normally, the hair germs would invaginate downwards into the dermis). This continued upward proliferation of follicle cells grossly perturbed the integrity of the conditional knockout epidermis postnatally. Even the down growth of older follicles, most likely established before Dicer depletion, also appear to be arrested. Whiskers were also malformed in these mice. Based on these observations, it is suggested that Dicer and its miRNA targets may be critical for regulating the epithelial-mesenchymal interactions that are essential for epidermal appendage development [115]. On the other hand, knocking out both Ago1/2 in mice (double knockout) resulted in sparse hair coat despite no obvious change in their post-natal survival ability. A closer examination showed that the hair follicle lineage in the Ago1/2 dKO mice was largely degenerated and the epidermis became hyperthickened. A comparison of the Ago1/2 dKO with Dicer cKO showed striking similarities in skin developmental defects such as the evaginating hair follicle cysts in the epidermis of P4 skin, shortened and misangled hair follicle growth etc., which can be attributed to the reduction of global miRNA expression in both cases.  However, the frequency of hair follicle cysts, and apoptotic cells in the proliferative basal epidermis was lower in the Ago1/2 dKO skin than the Dicer cKO skin. Taken together, our genetic analysis provides unambiguous evidence that neither Ago1 nor Ago2 (with its unique slicer activity) individually was essential for the functions of miRNAs during skin development [116].

Apart from the above studies, several reports have demonstrated the significance of individual microRNAs in hair follicle development and hair cycling. Recently, Yuan et al. (2015) reported miR-22, a highly conserved miRNA, to regulate hair follicle stem cell (HFSC) and progenitor cell expansion, migration, subsequent differentiation and hair shaft formation. In other words, miR-22 was found to be critical for the transition from growth to regression of the hair follicle [117]. Another miRNA that was found to be expressed at highest levels in HFSCs, particularly telogen stage HFSCs in both neonatal and adult skin, is miR-205. Genetic deletion of miR-205 caused neonatal lethality (KO animals usually died ~10 days after birth) with severely compromised epidermal and hair follicle growth. By P5, these KO animals became weaker and had less well-developed hair coats. Histology showed that the P4.5 skin had thinner epidermis, with short mis-angled hair follicles. Since miR-205 co-represses multiple negative regulators of the PI3K/Akt pathway, loss of miR-205 directly compromised the proliferation of HFSCs and interfollicular progenitors driving them to prematurely exit cell cycle and towards quiescence [118]. Key mediators of the Wnt signaling pathway, such as β-catenin and Lef1, are regulated by miR-214 thus implicating this particular miRNA in skin morphogenesis and hair follicle (HF) cycling. miR-214 exhibits differential expression patterns in the skin epithelium, and its inducible overexpression in keratinocytes inhibited proliferation, which resulted in the formation of fewer HFs with decreased hair bulb size and thinner hair production. Treatment with pharmacological Wnt activators rescued the above-mentioned consequences [119]. There is a possibility that some miRNAs like miR-203 may not be expressed at early stages of hair follicle development, but the expression intensifies in differentiating cells of epidermis along with its appendages, as development advances [120].

Future perspectives

  1. Drug discovery and delivery based on specific hair cycle or signaling anomaly.
  2. Future predictions for hair treatment and hence its avoidance.
  3. Based on different hair cycling ratios or even some other aspects, development of different mathematical models which might outline the progression of hair loss in androgen dependent or independent manner.
  4. Aging causes many stem cells to differentiate into skin cells through which we could isolate them, characterize them, and modulate or engineer them and then use them for hair retrieval. (taken from science paper).
  5. Using the above point if we could generate some kind of a progression of hair stem cell loss this could actually be quite novel because this might pave the way to replenish and maintain hair stem cell levels thus counteracting hair loss.
  6. People have long been using hair cosmetics but less do they know that using them leaves their hair in a worsened condition, therefore, this opens newer avenues which target hair as it is produced. This would require manipulating certain genes involved in hair coloration, patterning, morphology etc.


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16 and 17 from telogen effluvium (16. Olsen E. Androgenetic alopecia. In: Disorders of hair growth. New York, NY: McGraw-Hill, Inc; 1994. p. 257-83.                              17. Shapiro J. Diseases of the hair. In: Raykel R, editor. Conn’s current therapy. Philadelphia, Pa: WB Saunders; 1996. p. 739-41.)

Book: Progress in Monogenic Hair Disorders

Table 1: Hair disorders linked to desmosome gene mouse models and human diseases

Mutation/target gene Phenotype
Mouse Models
lah mouse (Desmoglein-4) “lanceolate hair,” generalized alopecia and hair shaft breakage
bal mouse (Desmoglein-3) “balding mouse,” alopecia and waves of hair shedding
Desmoglein-3 knockout Hairloss and epithelial fragility
Desmoplakin kockout Thinning of hair and abnormal follicles
Misexpression of desmocollin 3 (Suprabasally targeted) Flaky skin, defective epidermal barrier, hair loss. Patterned alopecia initiating with the first postnatal hair cycle
Human Diseases (Autosomal Recessive)
Plakoglobin carboxy-terminal truncation Naxos diease (arrythmogenic right ventricular cardiomyopathy, keratoderma and wooly hair)
Desmoplakin carboxy-terminal truncation/Desmoplakin I near ablation Arrythmogenic right ventricular cardiomyopathy, keratoderma and wooly hair
Plakophilin-1 ablation Skin-fragility – ectodermal dysplasia syndrome, hair loss
Desmoglein-4 ablation Inherited hypotrichosis
Human Diseases (Autosomal Dominant)
Carneodesmosin nonsense Hypotrichosis simplex of the scalp mutation

Book: Handbook of Mouse mutations with Skin and Hair Abnormalities: Animal Models – John P. Sundberg

Table 2: Mouse Hair and Skin Defects with Defines Genetic and Physiological basis which may be models for Human diseases

Mouse mutant gene Basic biochemical defect Human disease
FechmiPax Ferrochelatase deficiency Erythropoeitic protoporphyria
ic Reduced ultrahigh sulfur protein Trichothiodystrophy
lm Zinc binding protein Acrodermatitis enteropathica
Mobe Copper transport protein Menke’s disease
Otcspf, Otcash Ornithine transcarbamylase deficiency Two subsets of human ornithine transcarbomylase deficiency
Wa-1 Deficient TGF-a Wavy hair (?)

Pathophysiology responsible for most of the non-infectious diseases affecting human hair and skin are as yet unknown, and animal models can provide a major clue for the basis of such diseases. Many of the human diseases have a single locus responsible for the disorder which may act as a dominant or recessive disorder. There may be little assurance, a priori, that these complex disorders in man and rodents will have similar pathophysiologies. Although there are over 100 mutations in the mouse causing morphological abnormalities of the skin, hair, or hair loss, only a small number of these mutations have a defined biochemical basis. Furthermore, for many of these biochemically defined diseases, the functional consequences of the specific mutation are unknown.

Table 1: Examples of Human Genetic-Based Hair and Scalp Diseases

Disorders of hair or hair follicle structure

  • Menke’s syndrome
  • Monelithrix
  • Netherton’s syndrome with trichorrhexis nodosa
  • Pili torti (with associated syndromes)
  • Trichothiodystrophy

Inflammatory nonscarring hair loss

  • Alopecia areta

Scarring hair loss

  • Aplasia cutis
  • Incontientia pigmenti
  • Lamellar ichthyosis

Noninflammatory hair loss

  • Acrodermatitis enteropathica
  • Androgenetic alopecia
  • Anhidroitic epidermal dysplasia
  • Bazex’s syndrome
  • Biotin-responsive multiple carboxylase deficiency
  • Focal dermal hypoplasia
  • Hidrotic epidermal dysplasia
  • Myotonic dystrophy
  • Trichorhinophalengeal syndrome
  • Vitamin D resistant rickets-type II

Disorders of hair pigmentation

  • Albinism
  • Phenylketonuria
  • Piebaldism
  • Waardenburg’s syndrome

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