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Molecular design of hypothalamus development

Author

Listed:
  • Roman A. Romanov

    (Medical University of Vienna
    Biomedicum D7, Karolinska Institutet)

  • Evgenii O. Tretiakov

    (Medical University of Vienna)

  • Maria Eleni Kastriti

    (Medical University of Vienna
    Biomedicum D6, Karolinska Institutet)

  • Maja Zupancic

    (Medical University of Vienna)

  • Martin Häring

    (Medical University of Vienna)

  • Solomiia Korchynska

    (Medical University of Vienna)

  • Konstantin Popadin

    (Ecole Polytechnique Federale de Lausanne
    Immanuel Kant Baltic Federal University)

  • Marco Benevento

    (Medical University of Vienna)

  • Patrick Rebernik

    (Medical University of Vienna)

  • Francois Lallemend

    (Biomedicum D7, Karolinska Institutet)

  • Katsuhiko Nishimori

    (Fukushima Medical University)

  • Frédéric Clotman

    (Université Catholique de Louvain)

  • William D. Andrews

    (University College London)

  • John G. Parnavelas

    (University College London)

  • Matthias Farlik

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Medical University of Vienna)

  • Christoph Bock

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Medical University of Vienna)

  • Igor Adameyko

    (Medical University of Vienna
    Biomedicum D6, Karolinska Institutet)

  • Tomas Hökfelt

    (Biomedicum D7, Karolinska Institutet)

  • Erik Keimpema

    (Medical University of Vienna)

  • Tibor Harkany

    (Medical University of Vienna
    Biomedicum D7, Karolinska Institutet)

Abstract

A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus control the most fundamental physiological needs in vertebrates1,2. Nevertheless, we lack a developmental blueprint that integrates the molecular determinants of neuronal and glial diversity along temporal and spatial scales of hypothalamus development3. Here we combine single-cell RNA sequencing of 51,199 mouse cells of ectodermal origin, gene regulatory network (GRN) screens in conjunction with genome-wide association study-based disease phenotyping, and genetic lineage reconstruction to show that nine glial and thirty-three neuronal subtypes are generated by mid-gestation under the control of distinct GRNs. Combinatorial molecular codes that arise from neurotransmitters, neuropeptides and transcription factors are minimally required to decode the taxonomical hierarchy of hypothalamic neurons. The differentiation of γ-aminobutyric acid (GABA) and dopamine neurons, but not glutamate neurons, relies on quasi-stable intermediate states, with a pool of GABA progenitors giving rise to dopamine cells4. We found an unexpected abundance of chemotropic proliferation and guidance cues that are commonly implicated in dorsal (cortical) patterning5 in the hypothalamus. In particular, loss of SLIT–ROBO signalling impaired both the production and positioning of periventricular dopamine neurons. Overall, we identify molecular principles that shape the developmental architecture of the hypothalamus and show how neuronal heterogeneity is transformed into a multimodal neural unit to provide virtually infinite adaptive potential throughout life.

Suggested Citation

  • Roman A. Romanov & Evgenii O. Tretiakov & Maria Eleni Kastriti & Maja Zupancic & Martin Häring & Solomiia Korchynska & Konstantin Popadin & Marco Benevento & Patrick Rebernik & Francois Lallemend & Ka, 2020. "Molecular design of hypothalamus development," Nature, Nature, vol. 582(7811), pages 246-252, June.
  • Handle: RePEc:nat:nature:v:582:y:2020:i:7811:d:10.1038_s41586-020-2266-0
    DOI: 10.1038/s41586-020-2266-0
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    Citations

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    Cited by:

    1. Matthew C. Pahl & Claudia A. Doege & Kenyaita M. Hodge & Sheridan H. Littleton & Michelle E. Leonard & Sumei Lu & Rick Rausch & James A. Pippin & Maria Caterina Rosa & Alisha Basak & Jonathan P. Bradf, 2021. "Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Zsofia Hevesi & Joanne Bakker & Evgenii O. Tretiakov & Csaba Adori & Anika Raabgrund & Swapnali S. Barde & Martino Caramia & Thomas Krausgruber & Sabrina Ladstätter & Christoph Bock & Tomas Hökfelt & , 2024. "Transient expression of the neuropeptide galanin modulates peripheral‑to‑central connectivity in the somatosensory thalamus during whisker development in mice," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Solomiia Korchynska & Patrick Rebernik & Marko Pende & Laura Boi & Alán Alpár & Ramon Tasan & Klaus Becker & Kira Balueva & Saiedeh Saghafi & Peer Wulff & Tamas L. Horvath & Gilberto Fisone & Hans-Ulr, 2022. "A hypothalamic dopamine locus for psychostimulant-induced hyperlocomotion in mice," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. 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.
    5. Stéphane Leon & Vincent Simon & Thomas H. Lee & Lukas Steuernagel & Samantha Clark & Nasim Biglari & Thierry Lesté-Lasserre & Nathalie Dupuy & Astrid Cannich & Luigi Bellocchio & Philippe Zizzari & Ca, 2024. "Single cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Yingfeng Tao & Xiaoliu Zhou & Leqiang Sun & Da Lin & Huaiyuan Cai & Xi Chen & Wei Zhou & Bing Yang & Zhe Hu & Jing Yu & Jing Zhang & Xiaoqing Yang & Fang Yang & Bang Shen & Wenbao Qi & Zhenfang Fu & J, 2023. "Highly efficient and robust π-FISH rainbow for multiplexed in situ detection of diverse biomolecules," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. Tulsi Patel & Jennifer Hammelman & Siaresh Aziz & Sumin Jang & Michael Closser & Theodore L. Michaels & Jacob A. Blum & David K. Gifford & Hynek Wichterle, 2022. "Transcriptional dynamics of murine motor neuron maturation in vivo and in vitro," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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