Abstract
The hypothalamus is a central regulator of many innate behaviors essential for survival, but the molecular mechanisms controlling hypothalamic patterning and cell fate specification are poorly understood. To identify genes that control hypothalamic development, we have used single-cell RNA sequencing (scRNA-Seq) to profile mouse hypothalamic gene expression across 12 developmental time points between embryonic day 10 and postnatal day 45. This identified genes that delineated clear developmental trajectories for all major hypothalamic cell types, and readily distinguished major regional subdivisions of the developing hypothalamus. By using our developmental dataset, we were able to rapidly annotate previously unidentified clusters from existing scRNA-Seq datasets collected during development and to identify the developmental origins of major neuronal populations of the ventromedial hypothalamus. We further show that our approach can rapidly and comprehensively characterize mutants that have altered hypothalamic patterning, identifying Nkx2.1 as a negative regulator of prethalamic identity. These data serve as a resource for further studies of hypothalamic development, physiology, and dysfunction.
Highlights
The hypothalamus is a central regulator of many innate behaviors essential for survival, but the molecular mechanisms controlling hypothalamic patterning and cell fate specification are poorly understood
We focus on identifying genes that control hypothalamic regionalization and neurogenesis in the early embryo, and integrate these findings to generate a Hypothalamic Developmental Database (HyDD), which identifies selective markers of each region of the developing hypothalamus and prethalamus
To profile changes in gene expression across the full course of mouse hypothalamic development, we processed 12 time points ranging from embryonic day (E)[10] to postnatal day (P)[45]
Summary
The hypothalamus is a central regulator of many innate behaviors essential for survival, but the molecular mechanisms controlling hypothalamic patterning and cell fate specification are poorly understood. Previous efforts using microarray analysis coupled with large-scale two-color in situ hybridization (ISH) have identified a set of molecular markers that uniquely define spatial domains of the early embryonic hypothalamus and adjacent diencephalic regions[2], while parallel efforts using high-throughput ISH have identified additional region-specific markers[21,22] These datasets have been used as the basis for genetic studies that selectively disrupt the development of specific hypothalamic regions and/or cell types[23,24,25,26,27], leading to the identification of novel functions for previously characterized hypothalamic regions or cell types[28,29]. We demonstrate how the HyDD can be used to comprehensively analyze developmental mutants that generate complex phenotypes that would be difficult to characterize with traditional histology-based approaches, and in the process identify Nkx[] as a negative regulator of prethalamic identity
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