Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis

Keymeulen, Alexandra Van; Mascré, Guilhem; Youseff, Khalil Kass; Harel, Itamar; Michaux, Cindy; Geest, Natalie De; Szpalski, Caroline; Achouri, Younès; Bloch, Wilhelm; Hassan, Bassem; Blanpain, Cédric

doi:10.1084/jem20611oia26

Cited by 42 publications

(64 citation statements)

References 28 publications

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“…We speculate that the whisker follicle region has reached a maximum density in WT animals, and thus loss of Ezh1/2 has little consequence there. As expected, at P0, all Merkel cells co-express K18 and K20 ( Figure 1C) and in accordance with previous reports Morrison et al, 2009;Van Keymeulen et al, 2009;Woo et al, 2010), they lose expression of epidermal progenitor marker K5 ( Figure 1D). Merkel cells have been suggested to form near guard hair follicles, but histological analysis indicated no difference in the number of guard hair follicles present in Ezh1/2 2KO skin compared to WT (Supplementary Figure 1G), discounting the possibility that the observed phenotype was due to alterations in guard hair number.…”

Section: Loss Of Ezh1/2 Leads To Expansion Of Merkel Cellssupporting

confidence: 92%

“…Merkel cells were described over a century ago (Merkel, 1875) as clusters of cells located in touch-sensitive areas of the skin, where they transduce mechanical stimuli via sensory neurons to aid in the perception of curvature, texture, and shape of objects (Haeberle and Lumpkin, 2008). Consistent with this function, Merkel cells express voltagegated ion channels, neuropeptides, components of the presynaptic machinery such as Rab3c, and are innervated by sensory neurons; this is surprising, however, considering the epithelial origin of these cells Morrison et al, 2009;Van Keymeulen et al, 2009;Woo et al, 2010). The intermediate filament cytokeratins 18 and 20 (K18 and K20) are often used as a tool for the analysis and diagnosis of Merkel cell carcinoma due to their highly specific expression in Merkel cells (Houben et al, 2010;Donepudi et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells

Bardot

Valdés

Zhang

et al. 2013

EMBO J

107

133

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While the Polycomb complex is known to regulate cell identity in ES cells, its role in controlling tissue-specific stem cells is not well understood. Here we show that removal of Ezh1 and Ezh2, key Polycomb subunits, from mouse skin results in a marked change in fate determination in epidermal progenitor cells, leading to an increase in the number of lineage-committed Merkel cells, a specialized subtype of skin cells involved in mechanotransduction. By dissecting the genetic mechanism, we showed that the Polycomb complex restricts differentiation of epidermal progenitor cells by repressing the transcription factor Sox2. Ablation of Sox2 results in a dramatic loss of Merkel cells, indicating that Sox2 is a critical regulator of Merkel cell specification. We show that Sox2 directly activates Atoh1, the obligate regulator of Merkel cell differentiation. Concordantly, ablation of Sox2 attenuated the Ezh1/2-null phenotype, confirming the importance of Polycomb-mediated repression of Sox2 in maintaining the epidermal progenitor cell state. Together, these findings define a novel regulatory network by which the Polycomb complex maintains the progenitor cell state and governs differentiation in vivo.

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Section: Loss Of Ezh1/2 Leads To Expansion Of Merkel Cellssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells

Bardot

Valdés

Zhang

et al. 2013

EMBO J

107

133

View full text Add to dashboard Cite

show abstract

“…To characterize them and their relationship with nerve fibres, we used a battery of antibodies against specific cytoskeletal, synaptic vesicles, axons and Schwann cells, as Merkel cells form synaptic-like contacts with sensory afferent terminals (Llombart et al 2005; 2013; Fukuhara et al 2016). We demonstrated they are CK20, which is in line with the epithelial (Morrison et al 2009;Van Keymeulen et al 2009) and non-neural crest (Szeder et al 2003) origin of these cells. Nevertheless, we have also found NSE immunostaining in some Merkel cells, as previously reported (Masuda et al 1986;Isgr o et al 2015), which argues for a neuronal instead of epithelial origin.…”

Section: Discussionmentioning

confidence: 70%

Merkel cells and Meissner's corpuscles in human digital skin display Piezo2 immunoreactivity

et al. 2017

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The transformation of mechanical energy into electrical signals is the first step in mechanotransduction in the peripheral sensory nervous system and relies on the presence of mechanically gated ion channels within specialized sensory organs called mechanoreceptors. Piezo2 is a vertebrate stretch-gated ion channel necessary for mechanosensitive channels in mammalian cells. Functionally, it is related to light touch, which has been detected in murine cutaneous Merkel cell-neurite complexes, Meissner-like corpuscles and lanceolate nerve endings. To the best of our knowledge, the occurrence of Piezo2 in human cutaneous mechanoreceptors has never been investigated. Here, we used simple and double immunohistochemistry to investigate the occurrence of Piezo2 in human digital glabrous skin. Piezo2 immunoreactivity was detected in approximately 80% of morphologically and immunohistochemically characterized (cytokeratin 20 , chromogranin A and synaptophisin ) Merkel cells. Most of them were in close contact with Piezo2 nerve fibre profiles. Moreover, the axon, but not the lamellar cells, of Meissner's corpuscles was also Piezo2 , but other mechanoreceptors, i.e. Pacinian or Ruffini's corpuscles, were devoid of immunoreactivity. Piezo2 was also observed in non-nervous tissue, especially the basal keratinocytes, endothelial cells and sweat glands. The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner's corpuscles) low-threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch. These data offer additional insight into the molecular basis of mechanosensing in humans.

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“…25 Merkel cells undergo slow turnover and are replaced by cells originating from epidermal stem cells, not through proliferation of differentiated Merkel cells. 26 The TGF-b superfamily member Nodal, is involved in several developmental functions including left-right asymmetry during embryogenesis. 17 Additional roles for Nodal pathway are involvement in stem cell maintenance and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Lateral distribution of Merkel cell carcinoma in a nationwide cohort

Koljonen

Kluger

Sihto

et al. 2012

Acad Dermatol Venereol

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Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis

Cited by 42 publications

References 28 publications

Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells

Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells

Merkel cells and Meissner's corpuscles in human digital skin display Piezo2 immunoreactivity

Lateral distribution of Merkel cell carcinoma in a nationwide cohort

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