Abstract
Epidermal stratification of the mammalian skin requires proliferative basal progenitors to generate intermediate cells that separate from the basal layer and are replaced by post-mitotic cells. Although Wnt signaling has been implicated in this developmental process, the mechanism underlying Wnt-mediated regulation of basal progenitors remains elusive. Here we show that Wnt secreted from proliferative basal cells is not required for their differentiation. However, epidermal production of Wnts is essential for the formation of the spinous layer through modulation of a BMP-FGF signaling cascade in the dermis. The spinous layer defects caused by disruption of Wnt secretion can be restored by transgenically expressed Bmp4. Non-cell autonomous BMP4 promotes activation of FGF7 and FGF10 signaling, leading to an increase in proliferative basal cell population. Our findings identify an essential BMP-FGF signaling axis in the dermis that responds to the epidermal Wnts and feedbacks to regulate basal progenitors during epidermal stratification.
Highlights
Vertebrate epidermis, the outermost layer of skin, functions as a barrier for protection against environmental insult and dehydration
A thin layer of stratified epithelium forming the outmost surface of the skin, provides the crucial function to protect animals from environmental insults, such as bacterial pathogens and water loss. This barrier function is established in embryogenesis, during which single layered epithelial cells differentiate into distinct layers of keratinocytes
Wnt ligands have been implicated in hair follicle induction during skin development and self-renewal of stem cells in the interfollicular epidermis of adult skin; little is known about the mechanism of how Wnt signaling controls epidermal stratification during embryogenesis
Summary
Vertebrate epidermis, the outermost layer of skin, functions as a barrier for protection against environmental insult and dehydration. At approximately embryonic day 8.5 (E8.5) during mouse embryogenesis, the single-layered surface ectoderm adopts an epidermal developmental fate by turning off the expression of keratins 8 and 18 (K8/K18) and switching on the expression of K5/K14, leading to the replacement of the unspecified ectoderm by the embryonic basal layer [1,2]. The proliferative basal layer periodically produces intermediate suprabasal cells positive for K1/K10, programmed for terminal differentiation of keratinocytes [2]. The transient intermediate keratinocytes exit the cell cycle, followed by detachment from the basal layer and migration outward to form the spinous layer, characterized by the expression of K1 and K10. Subsequent developmental events engage the expression of differentiation genes, including loricrin and filaggrin, as spinous keratinocytes further develop into the granular and cornified layers contributing to barrier establishment at late embryonic stages
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