Physical interactions between Gsx2 and Ascl1 balance progenitor expansion versus neurogenesis in the mouse lateral ganglionic eminence

Development. 2020 Apr 10;147(7):dev185348. doi: 10.1242/dev.185348.

Abstract

The Gsx2 homeodomain transcription factor promotes neural progenitor identity in the lateral ganglionic eminence (LGE), despite upregulating the neurogenic factor Ascl1. How this balance in maturation is maintained is unclear. Here, we show that Gsx2 and Ascl1 are co-expressed in subapical progenitors that have unique transcriptional signatures in LGE ventricular zone (VZ) cells. Moreover, whereas Ascl1 misexpression promotes neurogenesis in dorsal telencephalic progenitors, the co-expression of Gsx2 with Ascl1 inhibits neurogenesis. Using luciferase assays, we found that Gsx2 reduces the ability of Ascl1 to activate gene expression in a dose-dependent and DNA binding-independent manner. Furthermore, Gsx2 physically interacts with the basic helix-loop-helix (bHLH) domain of Ascl1, and DNA-binding assays demonstrated that this interaction interferes with the ability of Ascl1 to bind DNA. Finally, we modified a proximity ligation assay for tissue sections and found that Ascl1-Gsx2 interactions are enriched within LGE VZ progenitors, whereas Ascl1-Tcf3 (E-protein) interactions predominate in the subventricular zone. Thus, Gsx2 contributes to the balance between progenitor maintenance and neurogenesis by physically interacting with Ascl1, interfering with its DNA binding and limiting neurogenesis within LGE progenitors.

Keywords: E-protein; Proximity ligation assay; Subapical progenitor; Tcf3; Telencephalon.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Brain / embryology*
  • Brain / metabolism
  • Cell Proliferation* / genetics
  • Cells, Cultured
  • Drosophila
  • Embryo, Mammalian
  • Female
  • Ganglia / cytology
  • Ganglia / embryology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Homeostasis / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Stem Cells / physiology*
  • Neurogenesis / physiology*
  • Protein Binding
  • Telencephalon / cytology
  • Telencephalon / embryology

Substances

  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Gsh2 protein, mouse
  • Homeodomain Proteins