Molecular design of hypothalamus development

A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus control the most fundamental physiological needs(1,2). Nevertheless, a developmental blueprint integrating molecular determinants of neuronal and glial diversity along temporal and spatial scales of hypothalamus development remains unresolved(3). Here, we combine single-cell RNA-seq on 51,199 cells of ectodermal origin, gene regulatory network (GRN) screens in conjunction with GWAS-based disease phenotyping and genetic lineage reconstruction to show that 9 glial and 33 neuronal subtypes are generated by mid-gestation under the control of distinct GRNs. Combinatorial molecular codes arising from neurotransmitters, neuropeptides and transcription factors are minimally required to decode the taxonomical hierarchy of hypothalamic neurons. Differentiation of GABA and dopamine but not glutamate neurons relies on quasi-stable intermediate states with a pool of GABA progenitors giving rise to dopamine cells(4). An unexpected abundance of chemotropic proliferation and guidance cues commonly implicated in dorsal (cortical) patterning(5) was found in the hypothalamus. Particularly, Slit/Robo loss-of-function impacted both the production and positioning of periventricular dopamine neurons. Overall, we uncover molecular principles shaping the developmental architecture of the hypothalamus and show how neuronal heterogeneity is transformed into a multimodal neural unit to endow a virtually infinite adaptive potential throughout life.