(1) Hypothalamus Development: From Neurogenesis to Circuit Assembly

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. We have been developing and applying sing-cell analysis approaches (single-cell lineage tracing, single-cell RNA-seq and single-cell genetic manipulation) to investigate how neurogenesis and nucleogenesis occur during hypothalamus development (Cell Stem Cell, 2021; Sci Adv, 2022; PLoS Biol, 2018). Given the diverse neuronal diversity, complex neuronal connection and critical neuronal function in the hypothalamus, more efforts are required to decode the processes and mechanisms of neuronal generation and circuit assembly.

(2) Hypothalamus Function, Hormones and Disorders

The hypothalamus secrets not only neurotransmitters and neuropeptides but also neurohormones to coordinate the interaction between brain and peripheral organs. Impaired neuronal fate determination and circuit assembly in the hypothalamus predisposes human beings to metabolic and endocrine disorders. To explore the physiological significance of hypothalamus development, we extensively investigate 1) novel neuronal subtypes regulating feeding behavior and body metabolism; 2) cellular mechanism underlying central precocious and delayed puberty (Sci Adv, 2022); and 3) genetic etiologies and pathological mechanisms of papillary craniopharyngioma (Nat Commun, 2021).

(3) Homeostatic regulation of neural stem cells

Homeostasis maintenance of neural stem/progenitor cells is critical for neural development, tumor initiation and neural regeneration. Homeostatic dysregulation of embryonic neural progenitor cells causes neural developmental disorders, such as autism and intellectual disability. Homeostatic disruption of adult neural stem cells may result in schizophrenia, mood disorder and progeria. We have been using lineage tracing and genomic editing approaches to investigate the molecular mechanisms underlying homeostatic regulation of neural stem/progenitor cells under physiological and pathological conditions (Dev Cell, 2023; Cell Rep, 2020; Cell, 2012).

(1) 下丘脑发育:从神经发生到环路组装

下丘脑通过调节内分泌、自主神经和行为功能来维持机体内稳态，包括饥饿、睡眠、体温、口渴、昼夜节律、情绪调节、性欲和激素释放等。然而，对于不同脊椎动物的下丘脑发育，包括其模式生成、神经发生和环路组装，我们却知之甚少。我们团队一直致力于开发和应用单细胞分析方法（包括单细胞谱系追踪、单细胞多组学和单细胞遗传操作等），用于研究下丘脑发育过程中神经发生和核团生成过程（Cell Stem Cell, 2021; Sci Adv, 2022; PLoS Biol, 2018）。由于下丘脑神经元种类的多样性、神经元连接的复杂性以及神经元功能的重要性，我们需要付出更多的努力来解码神经元生成和环路组装的过程和机制。

(2) 下丘脑功能、激素分泌与功能失调

下丘脑不仅分泌神经递质和神经肽，还分泌神经激素，用以协调大脑和外周器官之间的相互协作。如果下丘脑神经元命运决定和环路组装出现异常，会导致代谢失调和内分泌紊乱等疾病。为探讨下丘脑发育的生理意义，我们主要关注以下三方面的研究：1）调节进食行为和机体代谢的新型神经元亚型；2）中枢性早熟和青春期延迟的细胞机制 (Sci Adv, 2022)；3）乳头状颅咽管瘤的遗传病因和病理机制（Nat Commun, 2021）。

(3) 神经干细胞的稳态调节

神经干细胞的稳态维持对于神经发育和神经再生至关重要，胚胎期神经干细胞的稳态失调可以导致大脑发育异常，出现自闭症、智力障碍等疾病；成年期神经干细胞的稳态失调可以导致精神分裂症、情绪障碍、早衰等疾病。我们利用谱系追踪技术、基因编辑技术等研究在不同生理或病理条件下调控神经干细胞稳态的分子机制（Dev Cell, 2023; Cell Rep, 2020; Cell, 2012）。