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Review
. 2025 Dec;100(6):2738-2751.
doi: 10.1111/brv.70067. Epub 2025 Aug 12.

Molecular regulatory mechanisms of Merkel cell differentiation

Christian Felice Cervellera  1 , Chiara Mazziotta  1   2 , Elisa Mazzoni  3 , Ilaria Bononi  4 , Maria Rosa Iaquinta  1 , Mauro Tognon  1 , Fernanda Martini  1   2   5 , John Charles Rotondo  6
Affiliations
Review

Molecular regulatory mechanisms of Merkel cell differentiation

Christian Felice Cervellera et al. Biol Rev Camb Philos Soc. 2025 Dec.

Abstract

Merkel cells are specialized oval-shaped epithelial cells located in the basal epidermis and hair follicles, connected with afferent nerve endings responsible for sensory perception of light touch. Recent advances in developmental biology have shed light on the complex regulatory networks governing Merkel cell maturation. The most recent evidence indicates a crosstalk among epigenetic pathways, notably Polycomb multi-subunit complexes, Merkel cell-lineage transcription factors such as atonal BHLH transcription factor 1 (ATOH1), SRY-box transcription factor 2 (SOX2), ISL LIM homeobox 1 (ISL1) and additional players in the regulation of Merkel cell developmental programs. At the same time, the implications of dysregulated Merkel cell-lineage transcription factors during Merkel cell carcinoma (MCC) onset is under investigation. This review offers a comprehensive overview of the current understanding of the genetic and epigenetic pathways crucial for Merkel cell differentiation. It covers the implication of Merkel cell-specific developmental programs, the role of epigenetic regulatory Polycomb complexes, and how genetic and epigenetic mechanisms converge to orchestrate Merkel cell differentiation.

Keywords: Merkel cell carcinoma; Merkel cells; development; differentiation; epigenetic modifications; transcription factors.

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References

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