Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuron. 2021 Apr 7;109(7):1150-1167.e6. doi: 10.1016/j.neuron.2021.01.026. Epub 2021 Feb 17.
The hypothalamus plays crucial roles in regulating endocrine, autonomic, and behavioral functions via its diverse nuclei and neuronal subtypes. The developmental mechanisms underlying ontogenetic establishment of different hypothalamic nuclei and generation of neuronal diversity remain largely unknown. Here, we show that combinatorial T-box 3 (TBX3), orthopedia homeobox (OTP), and distal-less homeobox (DLX) expression delineates all arcuate nucleus (Arc) neurons and defines four distinct subpopulations, whereas combinatorial NKX2.1/SF1 and OTP/DLX expression identifies ventromedial hypothalamus (VMH) and tuberal nucleus (TuN) neuronal subpopulations, respectively. Developmental analysis indicates that all four Arc subpopulations are mosaically and simultaneously generated from embryonic Arc progenitors, whereas glutamatergic VMH neurons and GABAergic TuN neurons are sequentially generated from common embryonic VMH progenitors. Moreover, clonal lineage-tracing analysis reveals that diverse lineages from multipotent radial glia progenitors orchestrate Arc and VMH-TuN establishment. Together, our study reveals cellular mechanisms underlying generation and organization of diverse neuronal subtypes and ontogenetic establishment of individual nuclei in the mammalian hypothalamus.
下丘脑通过其多样的核和神经元亚型，在调节内分泌、自主和行为功能方面发挥着关键作用。不同下丘脑核的发生和神经元多样性产生的发育机制在很大程度上仍然未知。在这里，我们表明，组合 T 盒 3（TBX3）、同源盒转录因子（OTP）和远隔同源盒（DLX）的表达描绘了所有弓状核（Arc）神经元，并定义了四个不同的亚群，而组合 NKX2.1/SF1 和 OTP/DLX 的表达分别识别腹内侧下丘脑（VMH）和结节核（TuN）神经元亚群。发育分析表明，所有四个 Arc 亚群都是从胚胎期的 Arc 祖细胞中镶嵌和同时产生的，而谷氨酸能 VMH 神经元和 GABA 能 TuN 神经元是从共同的胚胎期 VMH 祖细胞中顺序产生的。此外，克隆谱系追踪分析揭示了多能放射状胶质祖细胞中的不同谱系协调了 Arc 和 VMH-TuN 的建立。总之，我们的研究揭示了哺乳动物下丘脑不同神经元亚型的产生和组织以及单个核的发生的细胞机制。
