Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3
(2024) Nature Communications — Vol. 15, n° 1, p. Published online (2024)
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- Authors
Keimpema, Erik 
Tretiakov, Evgenii O. Eder, Stephanie J. Renaux, Estelle Harkany, Tibor
- Abstract
- Acquisition of specialized cellular features is controlled by the ordered expression of transcription factors (TFs) along differentiation trajectories. Here, we find a member of the Onecut TF family, ONECUT3, expressed in postmitotic neurons that leave their Ascl1+/Onecut1/2+ proliferative domain in the vertebrate hypothalamus to instruct neuronal differentiation. We combined single-cell RNA-seq and gain-of-function experiments for gene network reconstruction to show that ONECUT3 affects the polarization and morphogenesis of both hypothalamic GABA-derived dopamine and thyrotropinreleasing hormone (TRH)+ glutamate neurons through neuron navigator-2 (NAV2). In vivo, siRNA-mediated knockdown of ONECUT3 in neonatal mice reduced NAV2 mRNA, as well as neurite complexity in Onecut3-containing neurons, while genetic deletion of Onecut3/ceh-48 in C. elegans impaired neurocircuit wiring, and sensory discrimination-based behaviors. Thus, ONECUT3, conserved across neuronal subtypes and many species, underpins the polarization and morphological plasticity of phenotypically distinct neurons that descend from a common pool of Ascl1+ progenitors in the hypothalamus.
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Zupančič, M., Keimpema, E., Tretiakov, E. O., Eder, S. J., Lev, I., Englmaier, L., Bhandari, P., Fietz, S. A., Härtig, W., Renaux, E., Villunger, A., Hökfelt, T., Zimmer, M., Clotman, F., & Harkany, T. (2024). Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3. Nature Communications, 15(1), Published online. https://doi.org/10.1038/s41467-024-52762-z (Original work published 2024)