Hypothalamus Development: From Neurogenesis to Circuit Assembly

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Background

Hypothalamus maintains systemic homeostasis by regulating endocrine, autonomic and behavioral functions, ranging from hunger, sleep, thirst, circadian rhythm and body temperature to mood regulation, sex drive and hormonal release. However, little is known about the hypothalamus development including its patterning, neurogenesis and circuit assembly across different vertebrate species. Consistent with general principles of brain development, hypothalamic induction and patterning require signaling from morphogens secreted by niche cells. Recently, transcription factors involved in hypothalamic neurogenesis and differentiation have been more and more identified. With the advent of single-cell technology, the molecular diversity, feature and design of hypothalamic neural progenitors and their progeny neurons have been generally revealed. Despite these striking progresses, the process of neuronal fate specification within the hypothalamus, which contains an astounding heterogeneity of neurons, and circuit assembly of various neuronal assemble remains enigmatic. Furthermore, the brain-wide connectome of hypothalamic neurons at mesoscale resolution and how the development of the hypothalamus regulates the overall neural wiring are also fundamentally important.

The goal of this Research Topic is to identify specific factors shaping the hypothalamus induction, regulating the hypothalamic neuronal differentiation and controlling the tempo of the hypothalamic circuit assembly, as well as understand the reciprocal regulation of neural wiring between the hypothalamus and other brain regions during development. To achieve these goals, we could apply cutting-edge techniques such as single-cell technology, spatial transcriptomics, lineage tracing, genetic perturbation and brain-wide reconstruction of the neural circuits to understand the patterning, neurogenesis and circuit formation of the hypothalamus. Here we take the patterning of the hypothalamus as an example. The early embryonic brains across different vertebrate species could be collected and subjected to spatial transcriptomic analysis for identifying specific patterning factors shaping the hypothalamus induction. Further functional validation may be required to confirm the role of patterning factors in the formation of the hypothalamus.

We welcome all submissions in the form of either Original Research or Reviews. This Research Topic will include, but not limited to, the following themes:

- Induction and Patterning of Hypothalamus
During hypothalamic induction and patterning, local niche signals along the rostrocaudal, dorsoventral and mediolateral axes could establish discrete hypothalamic subregions including preoptic, anterior, tuberal and mammillary zones and eventually help to define the boundaries of hypothalamic subregions.

- Formation of Hypothalamic Nuclei
The hypothalamus contains at least a dozen nuclei controlling diverse autonomic, endocrine and behavioral functions. However, the transcription factors regulating the establishment of distinct hypothalamic nuclei remain unclear.

- Factors Regulating Hypothalamic Neurogenesis
Hypothalamic neurons are comprised of magnocellular endocrine neurons, parvocellular secretory neurons, large peptidergic projection neurons, parvocellular neurons and other inhibitory or excitatory local-circuit neurons. Given the extreme neuronal heterogeneity within the hypothalamus, a systematic view of factors controlling the fate of hypothalamic neurons is still very vague.

- Circuit Assembly and Connectome of Hypothalamic Neurons
The connectome of hypothalamic neurons is extremely complex and the proper assembly of the hypothalamic circuit is fundamentally important for the systemic homeostasis of vertebrate organisms. For example, the connection between the arcuate nucleus and paraventricular nucleus drives the development of the hypothalamic feeding circuit, and a variety of factors such as leptin, ghrelin and nutrients have been reported to program the assembly of the feeding circuit and subsequently regulate the body metabolism.

- Heterogeneity and Function of Hypothalamic Tanycytes
The tanycytes along the third ventricle have recently identified as a third population of adult neural stem cells in the mammalian brain. The neurogenic potential of tanycytes and their function in regulating endocrine release and metabolism are very intriguing.

- Regulation of Overall Neural Wiring by Hypothalamus Development
A comprehensive understanding of overall neural wiring requires a developmental map of the brain connectome. Given the widespread and intensive connection between hypothalamic neurons and other brain regions, it is possible that hypothalamic neurons coordinate with other neuronal subtypes to direct or shape a subset of neural wiring. However, little is known about how the development of the hypothalamus may impact overall brain circuitry.

Keywords: Hypothalamus Development, Neural Patterning, Nucleus Formation, Fate Specification, Tanycytes

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