GFI1 controls Merkel cell survival through a dependence receptor pathway

Authors

• P Hallaert
• L Miao
• M Martin
• L Collado
• S Barkdull
• A Coxonm B Gyrder
• I Brownell

Abstract

Merkel cells (MCs) are touch sensors found in mammalian skin that bear both neuronal and epithelial features. Understanding their differentiation is crucial for modeling normal skin lineage commitment and elucidating the pathogenic mechanisms underlying Merkel cell carcinoma (MCC). Single-cell RNAseq revealed that the transcriptional repressor Gfi1 was increasingly expressed as MCs differentiated. We also found that MCs specifically expressed GFI1 in mouse skin. Gfli1 knockout mice produced a normal complement of MCs that were abnormally dendritic and rapidly underwent postnatal apoptosis. This dendritic morphology was consistent with our finding that genes involved in CNS development and neuronal differentiation were highly differentially expressed in GFI1-deficient neonatal MCs. Surprisingly, GFI1-deficient MCs also showed upregulation of the neuronal axon guidance receptor Dcc. This dependence receptor promotes cell survival when bound to its ligand, NTN1, and triggers apoptosis in its absence. Ntn1 was downregulated in our analysis. Knockout of Dcc significantly abrogated GFI1-deficient MC loss, demonstrating that suppression of dependence receptor signaling is an essential role of GFI1 in MC survival. Our findings also extended to MCC cell lines and tumors, where RNAseq verified the presence of GFI1 expression. Furthermore, CRISPR/Cas9-mediated GFI1 knockout killed MCC cells and ChIP-seq revealed that GFI1 bound the DCC gene locus, suggesting that GFI1 directly regulates DCC expression. Together, our findings shed light on the transcriptional regulation of MC differentiation and maintenance, and revealed functional parallels present in MCC pathogenesis.

Scientific Focus Area: Developmental Biology

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