The role of Engrailed1 in the regulation of the hair follicle and human thermoregulatory hair phenotype

ABSTRACT Vellus hairs are short and fine hairs that cover the human body and are essential for facilitating sweating, the major mechanism for human thermoregulatory cooling. Vellus hairs are formed during human gestation, in response to a shift in the growth cycle of human fetal hair follicles. During early fetal development, hair follicles first build large lanugo hairs, which are subsequently shed before birth. Starting around 20 weeks of gestation, fetal hair follicles undergo a reduction in the duration of their active growth phase (anagen), leading to the formation of smaller vellus hairs that predominate human skin post-partum. Determining the mechanisms that regulate the lanugo to vellus transition is critical in understanding the basis for this important thermoregulatory trait. A hallmark of the period that marks the onset of the lanugo to vellus transition in human fetal skin is the upregulated expression of a transcription factor, Engrailed1 (EN1). During this timeframe, EN1 expression is upregulated in multiple epidermal populations of the human fetal hair follicle, most notably in the hair matrix, the progenitor population from which the hair shaft derives. EN1 also becomes upregulated in the dermal papilla, the mesenchymal niche that regulates the hair cycle and hair production. In light of the concordance of EN1 upregulation and the onset of the lanugo to vellus transition, our lab turned to a humanized transgenic mouse model that allows for tunable En1 expression in the epidermis of the hair follicle in a manner consistent with human fetal skin. This model demonstrated that mice with ectopic En1 expression in the epidermis have shorter and thinner hairs due to a truncated growth phase (anagen) of the hair cycle, recapitulating key hair size diminution events observed during the lanugo to vellus transition. Considering these data, the hypothesis of this proposal is that En1 regulates hair size by altering the function of the hair matrix and the dermal papilla, two key populations involved in hair production. Accordingly, the aims of this proposal are to define the cellular and transcriptional mediators by which En1 functions in the two major skin compartments, epidermis (Aim 1) and dermal papilla (Aim 2), to alter hair follicle cycling. The proposed experiments will uncover the first mechanism underlying human vellus hair formation. Beyond their implications for understanding human-specific biology, the findings derived from this proposal will be critical for developing an integrative approach to comprehensive human skin regeneration.