Dlx1/2 are Central and Essential Components in the Transcriptional Code for Generating Olfactory Bulb Interneurons

Cereb Cortex. 2019 Dec 17;29(11):4831-4849. doi: 10.1093/cercor/bhz018.

Abstract

Generation of olfactory bulb (OB) interneurons requires neural stem/progenitor cell specification, proliferation, differentiation, and young interneuron migration and maturation. Here, we show that the homeobox transcription factors Dlx1/2 are central and essential components in the transcriptional code for generating OB interneurons. In Dlx1/2 constitutive null mutants, the differentiation of GSX2+ and ASCL1+ neural stem/progenitor cells in the dorsal lateral ganglionic eminence is blocked, resulting in a failure of OB interneuron generation. In Dlx1/2 conditional mutants (hGFAP-Cre; Dlx1/2F/- mice), GSX2+ and ASCL1+ neural stem/progenitor cells in the postnatal subventricular zone also fail to differentiate into OB interneurons. In contrast, overexpression of Dlx1&2 in embryonic mouse cortex led to ectopic production of OB-like interneurons that expressed Gad1, Sp8, Sp9, Arx, Pbx3, Etv1, Tshz1, and Prokr2. Pax6 mutants generate cortical ectopia with OB-like interneurons, but do not do so in compound Pax6; Dlx1/2 mutants. We propose that DLX1/2 promote OB interneuron development mainly through activating the expression of Sp8/9, which further promote Tshz1 and Prokr2 expression. Based on this study, in combination with earlier ones, we propose a transcriptional network for the process of OB interneuron development.

Keywords: Ascl1, Pax6; Dlx1; Dlx2; Gsx2; Sp8; Sp9; interneuron; olfactory bulb.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Female
  • Gene Expression Regulation, Developmental*
  • Homeodomain Proteins / metabolism*
  • Interneurons / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neocortex / embryology
  • Neocortex / metabolism
  • Neural Stem Cells / metabolism*
  • Olfactory Bulb / embryology
  • Olfactory Bulb / metabolism*
  • Transcription Factors / metabolism*

Substances

  • Distal-less homeobox proteins
  • Homeodomain Proteins
  • Transcription Factors