Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development

Carolina N. Perdigoto, Katherine L. Dauber, Carmit Bar, Pai Chi Tsai, Victor J. Valdes, Idan Cohen, Francis J. Santoriello, Dejian Zhao, Deyou Zheng, Ya Chieh Hsu, Elena Ezhkova

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere1006151
JournalPLoS Genetics
Volume12
Issue number7
DOIs
StatePublished - Jul 1 2016

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Merkel Cells
Erinaceidae
hair
skin (animal)
skin
Skin
Polycomb Repressive Complex 2
Hair Follicle
hair follicles
cells
Touch
touch (sensation)
ligand
dome
epigenetics
Cues
repression
niche
Genetic Epigenesis
Afferent Neurons

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Perdigoto, C. N., Dauber, K. L., Bar, C., Tsai, P. C., Valdes, V. J., Cohen, I., ... Ezhkova, E. (2016). Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development. PLoS Genetics, 12(7), [e1006151]. https://doi.org/10.1371/journal.pgen.1006151

Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development. / Perdigoto, Carolina N.; Dauber, Katherine L.; Bar, Carmit; Tsai, Pai Chi; Valdes, Victor J.; Cohen, Idan; Santoriello, Francis J.; Zhao, Dejian; Zheng, Deyou; Hsu, Ya Chieh; Ezhkova, Elena.

In: PLoS Genetics, Vol. 12, No. 7, e1006151, 01.07.2016.

Research output: Contribution to journalArticle

Perdigoto, CN, Dauber, KL, Bar, C, Tsai, PC, Valdes, VJ, Cohen, I, Santoriello, FJ, Zhao, D, Zheng, D, Hsu, YC & Ezhkova, E 2016, 'Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development', PLoS Genetics, vol. 12, no. 7, e1006151. https://doi.org/10.1371/journal.pgen.1006151
Perdigoto, Carolina N. ; Dauber, Katherine L. ; Bar, Carmit ; Tsai, Pai Chi ; Valdes, Victor J. ; Cohen, Idan ; Santoriello, Francis J. ; Zhao, Dejian ; Zheng, Deyou ; Hsu, Ya Chieh ; Ezhkova, Elena. / Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development. In: PLoS Genetics. 2016 ; Vol. 12, No. 7.
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