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Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3

Author

Listed:
  • 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
    Doctoral School of the University of Vienna and Medical 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
    Medical University of Innsbruck)

  • Tomas Hökfelt

    (Karolinska Institutet)

  • Manuel Zimmer

    (University of Vienna
    Vienna Biocenter (VBC))

  • Frédéric Clotman

    (Université catholique de Louvain)

  • Tibor Harkany

    (Medical University of Vienna
    Karolinska Institutet)

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.

Suggested Citation

  • 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 & To, 2024. "Concerted transcriptional regulation of the morphogenesis of hypothalamic neurons by ONECUT3," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52762-z
    DOI: 10.1038/s41467-024-52762-z
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    References listed on IDEAS

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