Embryonic maturation of epidermal Merkel cells is controlled by a redundant transcription factor network
Open accessAbstract
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.
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Merkel-like cells expressing key marker genes, such as ATOH1, KRT8/18, SOX2, and ISL1, were identified in the day-48 scRNA-seq dataset.
“Merkel-like cells expressing key marker genes, such as ATOH1, KRT8/18, SOX2, and ISL1, were also identified in our day-48 scRNA-seq dataset (Extended Data Fig. 6g)32.”
From Hair-bearing human skin generated entirely from pluripotent stem cells (2020) · cites this paper as [32]
SOX2+ nuclei speckles in the skin epithelium were Atoh1/nGFP+ ISL1+ cells that arose in the epithelium between days 14-16, reminiscent of Merkel cells.
“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).”
From Hair Follicle Development in Mouse Pluripotent Stem Cell-Derived Skin Organoids (2018) · cites this paper as Perdigoto et al., 2014
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Ferdous, A. S., Quitevis, E. J. A., Peterman, E., Sargent, S. M., Black, E. C., Dighe, S. M., & Rasmussen, J. P. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.16.752174
Zhang, Y., Yuan, H., Jiang, Y., Wang, T., Rui, C., Ding, Y., Wang, T., Wang, C., & Xiao, Y. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2603770123
- Authors
- Perdigoto, C. N., Bardot, E. S., Valdes, V. J., Santoriello, F. J., & Ezhkova, E.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Black Family Stem Cell Institute, Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Corresponding author
- Ezhkova, Elena
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2014-12-15
- Volume
- 141
- Issue
- 24
- Pages
- 4690-4696
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC4299268
- OpenAlex
- W1967319762
- Cited by
- 66
- References
- 24
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 5 · 2023: 7 · 2022: 3 · 2021: 5 · 2020: 8 · 2019: 9 · 2018: 5 · 2017: 3 · 2016: 5 · 2015: 1
- FWCI
- 1.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Università degli Studi di Milano
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR063724)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Tactile and Sensory Interactions
- Keywords
- Merkel cells, Merkel cell-neurite complexes, epidermal stem cells, embryonic development, Atoh1, SOX2, Isl1, transcriptional regulatory networks, tactile discrimination, tactile perception, skin
- MeSH terms
- Animals, Cell Differentiation, Fluorescent Antibody Technique, Humans, Indoles, Microscopy, Fluorescence, Skin, Transcription Factors, Blotting, Western, Gene Expression Regulation, Developmental, Merkel Cells, Immunoprecipitation, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Gene Regulatory Networks, SOXB1 Transcription Factors, LIM-Homeodomain Proteins
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