Desmogleins: hair perspective.

Desmogleins (Dsgs) are calcium-dependent, transmembrane glycoproteins belonging to the desmosomal cadherin superfamily, which play significant roles in selective calcium ions (Ca(2+)) dependent adhesion interactions between cell surfaces. Four subtypes of Dsg have been identified. Recent observations show the distribution of Dsgs can correlate with specific types of keratinization, anchorage of the hair, and hypotrichosis.

INTRODUCTION

Desmogleins (Dsgs) are calcium-dependent, type-1 transmembrane glycoproteins belonging to the desmosomal cadherin superfamily. They play significant role in selective calcium ions (Ca2+) dependent adhesion interactions between cell surfaces.[1] Currently, four subtypes of Dsg have been identified, namely, Dsg1, Dsg2, Dsg3, and Dsg4, and all of these Dsg gene family members are located in a cluster on chromosome 18.[2] Restriction enzyme analysis showed that the order of the Dsg genes and their orientation are as follows: 5-prime–Dsg1–Dsg3–Dsg2–3-prime.[3] In a multi-layered epithelium, different Dsgs are expressed in distinct patterns and may therefore, direct the process by which the different layers are specified.[45] Similar to the epidermis, the hair follicle (HF) is also compartmentalized into a hierarchy of cell types based on their level of differentiation.[6]

ROLE OF DSGS IN EPITHELIAL DIFFERENTIATION

Recent observations show the distribution of Dsgs can correlate with specific types of keratinization.[678] Dsg2 is expressed widely and is the predominant Dsg in simple epithelia, whereas, the other Dsgs are predominantly expressed in stratifying epithelia.[9] Dsg2 is less predominant in stratified squamous epithelia, found only in the basal cells, and may be a marker of less differentiated cells.[6] Dsg1 is present throughout the stratified squamous epithelia of the epidermis and oral mucosa, with increasing amounts as the cells differentiate toward the stratum corneum, and very little detectable in the basal layer.[6] This distribution suggests that the amount of Dsg1 correlates with the degree of differentiation.[6] Dsg3 is mainly distributed throughout the lower layers of the epidermis.[9] The distribution of Dsg3 also seems to correlate with the type of keratinization seen in the tissue in which it is expressed.[6] In epidermis, which has a typical “basket-weave” stratum corneum on routine histology, Dsg3 is localized to the basal and immediate suprabasal layers. While in oral mucous membrane, which has a characteristic compact lamellar stratum corneum, Dsg3 is expressed throughout the epithelium.[7] In transgenic mice in which there is forced expression of Dsg3 throughout the epidermis, the stratum corneum resembles that of mucosa.[10] Dsg4 is primarily expressed in the granular layer and in the HF.[9] The differential expression pattern of the Dsg implies that desmosomes within different tissues are biochemically, and presumably functionally, distinct and, it appears that the expression pattern of Dsg is critical to tissue homeostasis.[9]

Gene ablation studies have shown key roles for Dsg in development and in adult tissue function.[1112] Loss of mouse Dsg3 resulted in animals with compromised cell to cell adhesion in the oral mucosa with separation of keratinocytes and weakened desmosomal adhesion.[11] Ablation of Dsg2 results in embryonic lethality shortly after implantation.[12] This lethality on loss of Dsg2 was attributed in part to decreased embryonic stem cell proliferation, suggesting roles of Dsg2 that transcend desmosomal adhesive functions.[9] Misexpression of Dsg3 using the keratin 1 promoter to drive expression in the suprabasal epidermal layers in transgenic mice resulted in epidermal hyperproliferation and abnormal differentiation.[13] Furthermore, expressing Dsg3 in the upper layers of the epidermis using the involucrin promoter resulted in an even more severe phenotype including a resemblance to the oral mucosa, a reduction in epidermal barrier function, and early postnatal lethality because of extensive water loss.[8] Recently, Dsg2 misexpression in the differentiated layers of the epidermis was found to cause hyperproliferation and susceptibility to chemically induced carcinogenesis.[14] Absence of Dsg4 Leads to Epidermal Hyperproliferation.[15]

DSGS IN HAIR DIFFERENTIATION AND HAIR DISORDERS

Desmosomes are critical for the tissue integrity of stratified epithelia and their appendages.[16] Dsgs and desmocollins in desmosomes are transmembrane desmosomal cadherins that interact extracellularly to link neighboring epithelial cells.[16] The function of desmosomes in the normal structure and function of hair is still not very clear. The HF layers are morphologically distinct, desmosome-rich, cylindrical epithelial sheets that keratinize in a temporally autonomous pattern during anagen, and are each characterized by a distinct signature of hair keratins.[15]

Dsg expression patterns define compartments of cells in similar states of differentiation within the cutaneous epithelium and reveal a hierarchy of differentiation among these compartments.[6] Wu et al.[6] examined expression patterns of the Dsg isotypes, Dsgs 1, 2, and 3 in the cutaneous epithelium, and found that Dsg 1 and 2 expression correlated with the state of differentiation of defined populations within the HF. Dsg2 was highly expressed by the least differentiated cells of the cutaneous epithelium, including the HF bulge of the fetus and adult, bulb matrix cells, and basal layer of the outer root sheath (ORS). Dsg1, however, defined more differentiated cell populations, and was expressed in epidermal suprabasal cells, the inner root sheath (IRS), and the innermost layers of the ORS.[6] Wu et al.[6] also found the expression pattern of Dsg3 correlated with different types of keratinization. Dsg3 was expressed throughout all layers of the ORS and cyst wall in areas of trichilemmal keratinization in the follicle, and in cysts arising from these areas. In areas of epidermal-like keratinization, such as in the infundibulum and in epidermal inclusion cysts, Dsg3 expression was limited mainly to the basal layer.[6]

The HF bulge contains the least differentiated keratinocytes within the follicle and epidermis.[6] Ultrastructurally, bulge cells have fewer, less ordered, and thinner intermediate filament bundles compared with other basal the cells,[1718] which indicates a more immature phenotype as filament bundles generally become denser with maturation.[19] Dsg2 expression and absence of Dsg1 expression correlate with undifferentiated bulge cells.[6]

Knockout mice carrying mutations in Dsg3 lose their telogen hairs because of a defect in cell adhesion within the keratinocytes surrounding the club hair.[20] The role of Dsg1 and Dsg2 in the follicle is not yet clear. Based on the expression patterns, it was predicted that the loss of Dsg2 in the skin would result in major structural problems in the anagen and telogen HF, especially in the basal layer of the ORS at the level of the bulge and below.[6] The preferential expression of Dsg2 over the other Dsg proteins in these cells may indicate that, functionally, Dsg2 possesses unique characteristics required by more undifferentiated cells, including stem cells.[6]

IRS cells gradually acquire trichohyaline granules and eventually become corneocytes.[6] Biochemical analysis reveals that a major portion of the IRS structure is insoluble.[21] High levels of transglutaminase are present in IRS.[22] Various markers of differentiated cells in the epidermis such as Suprabasal keratin, K1 and K10, and involucrin, all markers of differentiated cells in the epidermis, are also present in the IRS.[2324] Strong Dsg1 expression and negativity for either Dsg2 or Dsg3 suggest that the IRS is more differentiated than any part of the ORS.[6] This is consistent with its highly specialized role in shaping the hair shaft.[6]

Mice without Dsg3 not only develop mucous membrane and skin lesions like pemphigus patients, but also develop hair loss.[20] Dsg3 anchors telogen hair in the follicle.[20] Dsg3 is not only critical for cell adhesion in the deep stratified squamous epithelium, but also for anchoring the telogen hair to the ORS of the follicle and underscore the importance of desmosomes in maintaining the normal structure and function of hair.[20]

Mutations in Dsg4 has been shown to cause hypotrichosis in the form of an inherited form of human hypotrichosis, and the lanceolate mouse models.[1525] Dsg4 is expressed in both the suprabasal epidermis and extensively throughout the matrix, pre-cortex, and IRS of the HF.[15] Dsg4 plays a key role in keratinocyte cell adhesion in the HF and in coordinating the transition from proliferation to differentiation in HF keratinocytes.[15] Kljuic et al.[15] also showed that Dsg4 participates in desmosomal junction with a highly specialized function during hair shaft differentiation. The maintenance of cell attachment is particularly critical during differentiation and hair growth.[26] The requirement of HF keratinocytes to smoothly transition from proliferation to differentiation, to resist shear forces as they ascend, and to differentiate along a different pathway than their neighbour is critically dependent on cell-cell attachment mediated in part by Dsg4.[15]

Anchorage of the hair to its follicle is of paramount importance for survival of rodents in the wild and is aberrant in some human alopecias.[27] The mechanisms responsible for hair shaft anchorage are not clearly understood. Dsg3−/− (knockout) mice lose hair during telogen, but their anagen hairs remain anchored to the follicle.[27] It was hypothesized that Dsg1 compensates for the loss of Dsg3 in the anagen HFs of these Dsg3−/− mice as Dsg1 and Dsg3 expression overlaps in the companion layer.[27]

CONCLUSION

Desmosomes are critical for the tissue integrity of stratified epithelia and their appendages. Little is known about the function of desmosomes in the normal structure and function of hair. Dsg expression patterns define compartments of cells in similar states of differentiation within the cutaneous epithelium and reveal a hierarchy of differentiation among these compartments.[6] Similarly, Dsg isotypes expression patterns correlate with the state of differentiation of defined populations within the HF.[6] Dsg 4 plays a key role in keratinocyte cell adhesion in the HF and in lanceolate hair (LAH).[15] The biological relevance of these findings extends into the area of skin autoimmunity since Dsg4 also serves as an autoantigen in patients with pemphigus vulgaris.[28] Whether the Dsgs are also involved in other alopecias, needs elucidation.