Engrailed transcription factors direct excitatory cerebellar neuron diversity and survival
Year: 2024
Type: article
Abstract: The neurons of the three cerebellar nuclei (CN) are the primary output neurons of the cerebellum. The excitatory neurons (e) of the medial (m) CN (eCNm) were recently divided into molecularly defined subdomains in the adult; however, how they are established during development is not known. We define molecular subdomains of the mouse embryonic eCNm using single-cell RNA-sequencing and spatial expression analysis, showing that they evolve during embryogenesis to prefigure the adult. Furthermore, eCNm are transcriptionally divergent from cells in the other nuclei by embryonic day 14.5. We previously showed that loss of the homeobox genes En1 and En2 leads to loss of approximately half of the embryonic eCNm. We demonstrate that mutation of En1/2 in the embryonic eCNm results in death of specific posterior eCNm molecular subdomains and downregulation of TBR2 (EOMES) in an anterior embryonic subdomain, as well as reduced synaptic gene expression. We further reveal a similar function for EN1/2 in mediating TBR2 expression, neuron differentiation and survival in the other excitatory neurons (granule and unipolar brush cells). Thus, our work defines embryonic eCNm molecular diversity and reveals conserved roles for EN1/2 in the cerebellar excitatory neuron lineage.
Source: Development
DOI: 10.1242/dev.202502
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: Memorial Sloan-Kettering Cancer Center, New York State Stem Cell Science, National Institutes of Health, Hunter College, National Institute of Mental Health, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Unraveling stem cell behaviors upon injury to the brain, Signaling Pathways that Regulate Scaling and Regeneration of the Cerebellum, G2971272634, G3528115037, Training Program in Developmental and Stem Cell Biology, Defining functional circuits between CN molecular subpopulations and the cerebral cortex, Engrailed genes and cerebellum morphology, spatial gene expression and circuitry, Cancer Center Support Grant, J. NRSA Training Core
OpenAlex ID: W4399976778