Molecular design of hypothalamus development

• Published in: Nature (London) Vol. 582; no. 7811; pp. 246 - 252
• Main Authors: Romanov, Roman A., Tretiakov, Evgenii O., Kastriti, Maria Eleni, Zupancic, Maja, Häring, Martin, Korchynska, Solomiia, Popadin, Konstantin, Benevento, Marco, Rebernik, Patrick, Lallemend, Francois, Nishimori, Katsuhiko, Clotman, Frédéric, Andrews, William D., Parnavelas, John G., Farlik, Matthias, Bock, Christoph, Adameyko, Igor, Hökfelt, Tomas, Keimpema, Erik, Harkany, Tibor
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2020; Nature Publishing Group
• Subjects: 13/51; 14/19; 38/43; 38/91; 42/109; 631/378/2571/1696; 631/378/2571/2573; 64/60; 82/1; Animals; Brain; Cell Differentiation; Cell Lineage; Combinatorial analysis; Dopamine; Dopamine - metabolism; Dopaminergic Neurons - cytology; Dopaminergic Neurons - metabolism; Ectoderm - cytology; Ectoderm - metabolism; Female; GABAergic Neurons - cytology; GABAergic Neurons - metabolism; gamma-Aminobutyric Acid - metabolism; Gene expression; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Gene sequencing; Genome-wide association studies; Genome-Wide Association Study; Genomes; Gestation; Glutamic Acid - metabolism; Heterogeneity; Humanities and Social Sciences; Hypothalamus; Hypothalamus - cytology; Hypothalamus - embryology; Hypothalamus - metabolism; Male; Medicin och hälsovetenskap; Mice; Morphogenesis; Morphogenesis - genetics; multidisciplinary; Nerve Tissue Proteins - metabolism; Neural stem cells; Neurogenesis; Neuroglia - cytology; Neuroglia - metabolism; Neuronal-glial interactions; Neurons; Neuropeptides; Neuropeptides - metabolism; Neurotransmitter Agents - metabolism; Neurotransmitters; Phenotyping; Physiological aspects; Receptors, Immunologic - metabolism; Regulon - genetics; Ribonucleic acid; RNA; Robo protein; Roundabout Proteins; Science; Science (multidisciplinary); Signal Transduction; Slit protein; Transcription factors; Transcription Factors - metabolism; γ-Aminobutyric acid; Austria
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-020-2266-0

A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus control the most fundamental physiological needs in vertebrates 1 , 2 . Nevertheless, we lack a developmental blueprint that integrates the molecular determinants of neuronal and glial diversity along temporal and spatial scales of hypothalamus development 3 . 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 cells 4 . We found an unexpected abundance of chemotropic proliferation and guidance cues that are commonly implicated in dorsal (cortical) patterning 5 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. Single-cell RNA sequencing reveals molecular determinants of the developmental programs that orchestrate the intermingling of neuronal subtypes in the hypothalamus.