A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel cell Development

An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures.

Author Summary Merkel cells are innervated touch-receptor cells that are responsible for light touch sensations. They originate from embryonic epidermal stem cells and, in hairy regions of skin, are organized in touch domes. Touch domes are highly patterned structures that form exclusively around primary hair follicles. Strikingly, the mechanisms controlling Merkel cell formation are largely unknown. Here, we show that the hair follicle functions as a niche required for Merkel cell formation. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh in the developing hair follicles, is required for Merkel cell specification, whereas Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to all hair types, suggesting that there are restrictive mechanisms that allow Merkel cell specification to occur exclusively around primary hairs. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis leads to the formation of ectopic Merkel cells around all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through derepression of key Merkel-differentiation genes; however, inductive Shh signaling is still required for the formation of mature Merkel cells. Our study illustrates how the interplay between epigenetic and morphogen cues functions to establish the complex patterning and formation of the mammalian skin.