A single-cell transcriptomic map of the developing Atoh1 lineage identifies neural fate decisions and neuronal diversity in the hindbrain

Dev Cell. 2024 Aug 19;59(16):2171-2188.e7. doi: 10.1016/j.devcel.2024.07.007. Epub 2024 Aug 5.

Abstract

Proneural transcription factors establish molecular cascades to orchestrate neuronal diversity. One such transcription factor, Atonal homolog 1 (Atoh1), gives rise to cerebellar excitatory neurons and over 30 distinct nuclei in the brainstem critical for hearing, breathing, and balance. Although Atoh1 lineage neurons have been qualitatively described, the transcriptional programs that drive their fate decisions and the full extent of their diversity remain unknown. Here, we analyzed single-cell RNA sequencing and ATOH1 DNA binding in Atoh1 lineage neurons of the developing mouse hindbrain. This high-resolution dataset identified markers for specific brainstem nuclei and demonstrated that transcriptionally heterogeneous progenitors require ATOH1 for proper migration. Moreover, we identified a sizable population of proliferating unipolar brush cell progenitors in the mouse Atoh1 lineage, previously described in humans as the origin of one medulloblastoma subtype. Collectively, our data provide insights into the developing mouse hindbrain and markers for functional assessment of understudied neuronal populations.

Keywords: Atoh1; CUT&RUN; DNA binding; brainstem; cerebellum; hindbrain; neural fate decisions; single-cell RNA sequencing; spatial transcriptomics.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors* / genetics
  • Basic Helix-Loop-Helix Transcription Factors* / metabolism
  • Cell Differentiation
  • Cell Lineage* / genetics
  • Cell Movement
  • Gene Expression Regulation, Developmental
  • Mice
  • Neurogenesis / genetics
  • Neurons* / cytology
  • Neurons* / metabolism
  • Rhombencephalon* / cytology
  • Rhombencephalon* / metabolism
  • Single-Cell Analysis* / methods
  • Transcriptome* / genetics

Substances

  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors