Embryonic maturation of epidermal Merkel cells is controlled by a redundant transcription factor network

Abstract

Merkel cell-neurite complexes are located in touch-sensitive areas of the mammalian skin and are involved in recognition of the texture and shape of objects. Merkel cells are essential for these tactile discriminations, as they generate action potentials in response to touch stimuli and induce the firing of innervating afferent nerves. It has been shown that Merkel cells originate from epidermal stem cells, but the cellular and molecular mechanisms of their development are largely unknown. In this study, we analyzed Merkel cell differentiation during development and found that it is a temporally regulated maturation process characterized by a sequential activation of Merkel cell-specific genes. We uncovered key transcription factors controlling this process and showed that the transcription factor Atoh1 is required for initial Merkel cell specification. The subsequent maturation steps of Merkel cell differentiation are controlled by cooperative function of the transcription factors Sox2 and Isl1, which physically interact and work to sustain Atoh1 expression. These findings reveal the presence of a robust transcriptional network required to produce functional Merkel cells that are required for tactile discrimination.

EctopicAtoh1expression drives Merkel cell production in embryonic, postnatal and adult epidermis

“…This is consistent with the observation that Sox2+ epidermal cells are absent from the skin of Atoh1-null mice (Perdigoto et al, 2014). Upregulation of Sox2 and Isl1 combined with Atoh1 autoregulation (Helms et al, 2000) might contribute to maintained Atoh1 expression seen following Atoh1 transgene silencing.…”

“…We wondered whether ectopic Atoh1 expression drove expression of Merkel cell markers other than K8. We looked first at expression of Sox2 and Isl1, two transcription factors expressed early in Merkel cell development (Bardot et al, 2013;Lesko et al, 2013;Perdigoto et al, 2014). The vast majority of ectopic K8+ cells co-expressed Sox2 and Isl1 at 4 days and 2 weeks post-doxycycline ( Fig.…”

Hair Follicle Development in Mouse Pluripotent Stem Cell-Derived Skin Organoids

“…The majority of SG-like structures observed in the skin organoids were bifurcates, reminiscence of guard hairs (Driskell et al, 2009). Moreover, as mentioned earlier in Figure 4D′, the SOX2 + nuclei speckles in the skin epithelium were Atoh1/nGFP + ISL1 + cells that arose in the epithelium between days 14–16 (Figure 5F–F″), reminiscence of Merkel cells, which are touch sensing cells in the epidermis (Lumpkin et al, 2003; Perdigoto et al, 2014). However, these cells were rarely seen after approximately day 20 of differentiation (data not shown).…”

The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons

“…Notably, Isl1 has been shown to drive fate specification of many cell types during multiple tissue development, often by forming cell type-specific complexes with various partner transcription factors. For instance, Isl1 partners with the LIM-HD factor Lhx3 in specifying motor neurons in the spinal cord (Thaler et al, 2002;Lee and Pfaff, 2003), the LIM-HD factor Lhx8 in directing the fate of forebrain cholinergic neurons in the ventral telencephalon (Cho et al, 2014), the HD factor Phox2a in cranial motor neurons (Mazzoni et al, 2013), the basic helix-loop-helix transcription factor Beta2 (Neurod1) in pancreas (Peng et al, 2005), the high-mobility group box factor Sox2 in epidermal Merkel cells (Perdigoto et al, 2014) and the POU-domain transcription factor Pou4f2 in retinal ganglion cells (Li et al, 2014). Given these results, it is probable that Isl1 forms distinct cell type-specific complexes in AgRP-, POMC-, GHRH-and Sst-neurons in the ARC, which enable Isl1 to control distinct sets of target genes in each neuronal type in the developing hypothalamus.…”

“…Islet-1 (Isl1), a member of the LIM-homeodomain (LIM-HD) transcription factor family, has been shown to regulate cell fate specification in multiple tissues and species (Thaler et al, 2002;Lee and Pfaff, 2003;Peng et al, 2005;Mazzoni et al, 2013;Cho et al, 2014;Li et al, 2014;Perdigoto et al, 2014). Here, we report that Isl1 plays crucial roles in the development of multiple ARC neurons, which control feeding and linear growth.…”