Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3

Maja Zupančič, Erik Keimpema (), Evgenii O. Tretiakov, Stephanie J. Eder, Itamar Lev, Lukas Englmaier, Pradeep Bhandari, Simone A. Fietz, Wolfgang Härtig, Estelle Renaux, Andreas Villunger, Tomas Hökfelt, Manuel Zimmer, Frédéric Clotman and Tibor Harkany ()
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Maja Zupančič: Medical University of Vienna
Erik Keimpema: Medical University of Vienna
Evgenii O. Tretiakov: Medical University of Vienna
Stephanie J. Eder: University of Vienna
Itamar Lev: University of Vienna
Lukas Englmaier: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Pradeep Bhandari: Institute of Science and Technology Austria
Simone A. Fietz: University of Leipzig
Wolfgang Härtig: University of Leipzig
Estelle Renaux: Université catholique de Louvain
Andreas Villunger: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Tomas Hökfelt: Karolinska Institutet
Manuel Zimmer: University of Vienna
Frédéric Clotman: Université catholique de Louvain
Tibor Harkany: Medical University of Vienna

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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 thyrotropin-releasing 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.

Date: 2024
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DOI: 10.1038/s41467-024-52762-z

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