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Molecular design of hypothalamus development

Roman A. Romanov, Evgenii O. Tretiakov, Maria Eleni Kastriti, Maja Zupancic, Martin Häring, Solomiia Korchynska, Konstantin Popadin, Marco Benevento, Patrick Rebernik, Francois Lallemend, Katsuhiko Nishimori, Frédéric Clotman, William D. Andrews, John G. Parnavelas, Matthias Farlik, Christoph Bock, Igor Adameyko, Tomas Hökfelt, Erik Keimpema and Tibor Harkany ()
Additional contact information
Roman A. Romanov: Medical University of Vienna
Evgenii O. Tretiakov: Medical University of Vienna
Maria Eleni Kastriti: Medical University of Vienna
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
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
Christoph Bock: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Igor Adameyko: Medical University of Vienna
Tomas Hökfelt: Biomedicum D7, Karolinska Institutet
Erik Keimpema: Medical University of Vienna
Tibor Harkany: Medical University of Vienna

Nature, 2020, vol. 582, issue 7811, 246-252

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2266-0

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