FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells

Abstract

Merkel cells are innervated mechanosensory cells responsible for light-touch sensations. In murine dorsal skin, Merkel cells are located in touch domes and found in the epidermis around primary hairs. While it has been shown that Merkel cells are skin epithelial cells, the progenitor cell population that gives rise to these cells is unknown. Here, we show that during embryogenesis, SOX9-positive (+) cells inside hair follicles, which were previously known to give rise to hair follicle stem cells (HFSCs) and cells of the hair follicle lineage, can also give rise to Merkel Cells. Interestingly, while SOX9 is critical for HFSC specification, it is dispensable for Merkel cell formation. Conversely, FGFR2 is required for Merkel cell formation but is dispensable for HFSCs. Together, our studies uncover SOX9(+) cells as precursors of Merkel cells and show the requirement for FGFR2-mediated epithelial signalling in Merkel cell specification.

Dissection of Merkel cell formation in hairy and glabrous skin reveals a common requirement for FGFR2‐mediated signalling

“…We treated embryos with tamoxifen at E13.5‐E14.5, when Merkel cells had not yet been specified, and collected paws and back skins at E17.5 (Figure E). Immunofluorescence analysis showed that GFP staining was found in approximately 85% of KRT8(+) Merkel cells in the back skin (Figure F, G), which is consistent with our previous report that showed that Merkel cells originate from SOX9(+) precursor cells in the back skin . In contrast, KRT8(+) Merkel cells were not GFP(+) in the glabrous paw skin (Figure H, I; Figure C).…”

“…We collected paws from Atoh1‐GFP pups at embryonic day (E) 14.5, E15.5, E16.5 and postnatal day (P) 0 and performed immunofluorescence analyses of ATOH1‐GFP and the keratin intermediate filaments 8 and 20 (KRT8 and KRT20, respectively) that are expressed in more mature Merkel cells . At E14.5, when Merkel cells were already formed inside of the hair placode of the back skin, we could not detect any ATOH1‐GFP(+), KRT8(+) or KRT20(+) Merkel cells in the mouse paw (Figure A). At E15.5, a few ATOH1‐GFP(+) and KRT8(+) Merkel cells were observed in the mouse paw (Figure B).…”

“…In the back skin, we previously found that Merkel cells formed from SOX9(+) cells present in primary hair placodes . Therefore, we sought to determine whether Merkel cells in glabrous skin are also formed from SOX9(+) cells.…”

“…Most of our knowledge about Merkel cells comes from studies focused on the murine back skin, where these cells are found in specialized structures called touch domes which are located exclusively around primary hair follicles . Recently, we discovered that a subset of SOX9‐expressing cells located inside of developing hair follicles are Merkel cell progenitors that give rise to Merkel cells at embryonic day (E) 14.5 . We also found that fibroblast growth factor receptor 2 (FGFR2) plays an essential function in Merkel cell specification in the back skin, as loss of Fgfr2 leads to drastic decreases in the number of Merkel cells but does not affect the formation of SOX9‐positive (+) cells .…”

“…Recently, we discovered that a subset of SOX9‐expressing cells located inside of developing hair follicles are Merkel cell progenitors that give rise to Merkel cells at embryonic day (E) 14.5 . We also found that fibroblast growth factor receptor 2 (FGFR2) plays an essential function in Merkel cell specification in the back skin, as loss of Fgfr2 leads to drastic decreases in the number of Merkel cells but does not affect the formation of SOX9‐positive (+) cells . To further our investigations, we sought to determine whether our recent findings in the murine back skin apply to other types of skin in the mouse such as the glabrous skin.…”