Epigenetic and genetic reprogramming during embryonic chicken feather bud morphogenesis, hair morphogenesis, and de novo hair regeneration

The ability to engineer a tissue to replace diseased organs is a goal that when achieved will provide an incredible asset to clinicians. In order to engineer a tissue, one must understand how the specific tissue develops, maintains homeostasis, and regenerates. To gain insight into this process, we utilized the embryonic chicken skin organ (CSO) model to study the effect of histone acetylation and methylation on feather bud development. In the CSO assay, Chaetocin, a histone methyltransferase inhibitor, acts upstream of FGF and BMP to promote feather bud growth. MS275, a histone deacetylase inhibitor, acts upstream of FGF and BMP to inhibit feather bud growth. Next, we employed a tissue specific transgenic mouse model to investigate the effect of HDAC1 on mouse skin morphogenesis. Immunostaining of wild type C57BL/6 skin showed HDAC1 is predominantly located in the epidermal basal layer, sebaceous glands, inner and outer root sheaths, and matrix of pelage and vibrissae hair follicles. K14creHDAC1fl/fl mice exhibited a reduction in size and weight, hyperkeratosis, alopecia, dermal cysts, hyperpigmentation, sebaceous hyperplasia and nail pathologies including; supernumeray nails, elongated nails, and pigmented nail plates. Finally, we studied hair follicle regeneration to examine how Msx2 modulates de novo hair growth. Full thickness, large wounds (> 1.5cm in diameter) were created on the dorsum of wild type (C57bl/6), Msx2LacZ (1.7KB, 560bp and 52bp), Msx2-/-, and K14creMsx2 fl/fl mice. Msx2 expression occurred in two phases: early in the wound margin and later, as a punctate pattern in the center wound bed. Genetic ablation of Msx2 inhibits de novo hair regeneration in both totally null (Msx2 -/-) or tissue specific (K14creMsx2 fl/fl) null mice. An Msx2 promoter with a mutation of the Mad/Smad factor binding site failed to induce Msx2 expression in the wound. However, K14noggin mice showed only a slight increase in de novo hair regeneration, suggesting BMP alone is insufficient and more complex regulation is used to control Msx2. Taken together, these data suggest a hierarchy of gene expression mechanisms that govern tissue specific structure and function. Epigenetic and genetic mechanisms modulate gene expression patterns resulting in spacio-temporal control of tissue competence and morphogenesis.