Identification of Pappa and Sall3 as Gli3 direct target genes acting downstream of cilia signalling in corticogenesis

The cerebral cortex is critical for advanced cognitive functions and relies on a vast network of neurons to carry out its highly intricate neural tasks. Generating cortical neurons in accurate numbers hinges on cell signalling orchestrated by primary cilia to coordinate the proliferation and differentiation of cortical stem cells. While recent research has shed light on multiple ciliary roles in corticogenesis, specific mechanisms downstream of cilia signalling remain largely unexplored. We previously showed that an excess of early-born cortical neurons in mice mutant for the ciliary gene Inpp5e was rescued by re-introducing Gli3 repressor. By comparing expression profiles between Inpp5e and Gli3 mutants, we here identified novel Gli3 target genes. This approach highlighted the transcription factor gene Sall3 and Pappalysin1 (Pappa), a metalloproteinase involved in IGF signalling, as up-regulated genes. Further examination revealed that Gli3 directly binds to Sall3 and Pappa enhancers and suppresses their activity in the dorsal telencephalon. Collectively, our analyses provide important mechanistic insights into how primary cilia govern the behaviour of neural stem cells, ultimately ensuring the production of adequate numbers of neurons during corticogenesis. SUMMARY STATEMENTThis study reports how cilia control gene expression via Gli3 in the developing murine cerebral cortex.