GemC1 controls multiciliogenesis in the airway epithelium

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Abstract
Multiciliated cells are terminally differentiated, post‐mitotic cells that form hundreds of motile cilia on their apical surface. Defects in multiciliated cells lead to disease, including mucociliary clearance disorders that result from ciliated cell disfunction in airways. The pathway controlling multiciliogenesis, however, remains poorly characterized. We showed that GemC1, previously implicated in cell cycle control, is a central regulator of ciliogenesis. GemC1 is specifically expressed in ciliated epithelia. Ectopic expression of GemC1 is sufficient to induce early steps of multiciliogenesis in airway epithelial cells ex vivo, upregulating McIdas and FoxJ1, key transcriptional regulators of multiciliogenesis. GemC1 directly transactivates the McIdas and FoxJ1 upstream regulatory sequences, and its activity is enhanced by E2F5 and inhibited by Geminin. GemC1‐knockout mice are born with airway epithelia devoid of multiciliated cells. Our results identify GemC1 as an essential regulator of ciliogenesis in the airway epithelium and a candidate gene for mucociliary disorders. Synopsis GemC1 is required for the differentiation of multiciliated airway epithelial cells. It induces McIdas and FoxJ1 expression, promoting early steps of ciliogenesis. GemC1 is specifically expressed in ciliated epithelia, and its ectopic expression is sufficient to induce McIdas and Foxj1, the earliest known transcriptional regulators of ciliogenesis. GemC1 directly transactivates the promoters of MCIDAS and FOXJ1. It co‐operates with E2F5 and is inhibited by geminin. Mice deficient for GemC1 are born with airway epithelia devoid of multiciliated cells, exhibit severe postnatal growth retardation, and die soon after birth.
Funding Information
  • European Research Council (DYNACOM 281851)

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