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

Cereb Cortex. 2024 Dec 3;34(12):bhae480. doi: 10.1093/cercor/bhae480.

Abstract

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 signaling 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 signaling 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 signaling, as upregulated genes in both mutants. 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 behavior of neural stem cells, ultimately ensuring the production of adequate numbers of neurons during corticogenesis.

Keywords: Gli3; Inpp5e; Pappa; Sall3; corticogenesis; primary cilia.

MeSH terms

  • Animals
  • Cerebral Cortex* / cytology
  • Cerebral Cortex* / embryology
  • Cerebral Cortex* / metabolism
  • Cilia* / metabolism
  • Cilia* / physiology
  • Gene Expression Regulation, Developmental
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins* / genetics
  • Nerve Tissue Proteins* / metabolism
  • Neural Stem Cells / metabolism
  • Neurogenesis* / physiology
  • Neurons / metabolism
  • Signal Transduction* / physiology
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Zinc Finger Protein Gli3* / genetics
  • Zinc Finger Protein Gli3* / metabolism

Substances

  • Zinc Finger Protein Gli3
  • Gli3 protein, mouse
  • Transcription Factors
  • Nerve Tissue Proteins