Transcriptional dynamics orchestrating the development and integration of neurons born in the adult hippocampus

Sci Adv. 2024 Jul 19;10(29):eadp6039. doi: 10.1126/sciadv.adp6039. Epub 2024 Jul 19.

Abstract

The adult hippocampus generates new granule cells (aGCs) with functional capabilities that convey unique forms of plasticity to the preexisting circuits. While early differentiation of adult radial glia-like cells (RGLs) has been studied extensively, the molecular mechanisms guiding the maturation of postmitotic neurons remain unknown. Here, we used a precise birthdating strategy to study aGC differentiation using single-nuclei RNA sequencing. Transcriptional profiling revealed a continuous trajectory from RGLs to mature aGCs, with multiple immature stages bearing increasing levels of effector genes supporting growth, excitability, and synaptogenesis. Analysis of differential gene expression, pseudo-time trajectory, and transcription factors (TFs) revealed critical transitions defining four cellular states: quiescent RGLs, proliferative progenitors, immature aGCs, and mature aGCs. Becoming mature aGCs involved a transcriptional switch that shuts down pathways promoting cell growth, such SoxC TFs, to activate programs that likely control neuronal homeostasis. aGCs overexpressing Sox4 or Sox11 remained immature. Our results unveil precise molecular mechanisms driving adult RGLs through the pathway of neuronal differentiation.

MeSH terms

  • Animals
  • Cell Differentiation* / genetics
  • Ependymoglial Cells / cytology
  • Ependymoglial Cells / metabolism
  • Gene Expression Profiling
  • Hippocampus* / cytology
  • Hippocampus* / metabolism
  • Mice
  • Neurogenesis* / genetics
  • Neurons* / cytology
  • Neurons* / metabolism
  • SOXC Transcription Factors* / genetics
  • SOXC Transcription Factors* / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic

Substances

  • SOXC Transcription Factors
  • Sox4 protein, mouse
  • Sox11 protein, mouse
  • Transcription Factors