Engrailed transcription factors direct excitatory cerebellar neuron diversity and survival Journal Article
| Authors: | Krishnamurthy, A.; Lee, A. S.; Sumru Bayin, N.; Stephen, D. N.; Nasef, O.; Lao, Z.; Joyner, A. L. |
| Article Title: | Engrailed transcription factors direct excitatory cerebellar neuron diversity and survival |
| 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. © 2024. Published by The Company of Biologists Ltd. |
| Keywords: | adult; controlled study; protein expression; gene mutation; genetics; nonhuman; animal cell; mouse; animal; cytology; metabolism; animals; mice; animal tissue; cerebellum; cell survival; gene expression; embryo; animal experiment; nerve tissue proteins; embryo development; embryology; gene function; cell differentiation; homeodomain proteins; neurons; immunofluorescence; gene expression regulation; in situ hybridization; gene expression regulation, developmental; granule cell; down regulation; upregulation; transcription factor pax6; homeodomain protein; nerve protein; nerve cell differentiation; nerve cell; fluorescence activated cell sorting; marker gene; mouse embryo; cerebellum nucleus; cerebellar nuclei; synapse; nerve cell necrosis; t box transcription factor; granule cell precursors; single cell analysis; single-cell analysis; brain tissue; eomesodermin; homeobox; t-box domain proteins; en1; en2; engrailed 2 protein; unipolar brush cells; nerve cell excitability; female; article; tunel assay; brush border; single cell rna seq; eomes; tbr1; en1 protein, mouse; barhl1 gene; calb2 gene; en1 gene; en2 gene; lmx1a gene; tbr1 gene |
| Journal Title: | Development |
| Volume: | 151 |
| Issue: | 14 |
| ISSN: | 0950-1991 |
| Publisher: | Company of Biologists |
| Date Published: | 2024-07-01 |
| Start Page: | dev202502 |
| Language: | English |
| DOI: | 10.1242/dev.202502 |
| PUBMED: | 38912572 |
| PROVIDER: | scopus |
| PMCID: | PMC11369685 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Alexandra L. Joyner -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work