Department of Neuroscience, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
J Neurosci. 2020 Apr 29;40(18):3549-3563. doi: 10.1523/JNEUROSCI.2610-19.2020. Epub 2020 Apr 9.
The tuberal hypothalamus is comprised of the dorsomedial, ventromedial, and arcuate nuclei, as well as parts of the lateral hypothalamic area, and it governs a wide range of physiologies. During neurogenesis, tuberal hypothalamic neurons are thought to be born in a dorsal-to-ventral and outside-in pattern, although the accuracy of this description has been questioned over the years. Moreover, the intrinsic factors that control the timing of neurogenesis in this region are poorly characterized. Proneural genes, including () and () are widely expressed in hypothalamic progenitors and contribute to lineage commitment and subtype-specific neuronal identifies, but the potential role of Neurogenin 2 (Neurog2) remains unexplored. Birthdating in male and female mice showed that tuberal hypothalamic neurogenesis begins as early as E9.5 in the lateral hypothalamic and arcuate and rapidly expands to dorsomedial and ventromedial neurons by E10.5, peaking throughout the region by E11.5. We confirmed an outside-in trend, except for neurons born at E9.5, and uncovered a rostrocaudal progression but did not confirm a dorsal-ventral patterning to tuberal hypothalamic neuronal birth. In the absence of , neurogenesis stalls, with a significant reduction in early-born BrdU cells but no change at later time points. Further, the loss of yielded a similar delay in neuronal birth, suggesting that cannot rescue the loss of and that these proneural genes act independently in the tuberal hypothalamus. Together, our findings show that functions as a classical proneural gene to regulate the temporal progression of tuberal hypothalamic neurogenesis. Here, we investigated the general timing and pattern of neurogenesis within the tuberal hypothalamus. Our results confirmed an outside-in trend of neurogenesis and uncovered a rostrocaudal progression. We also showed that acts as a classical proneural gene and is responsible for regulating the birth of early-born neurons within the ventromedial hypothalamus, acting independently of In addition, we revealed a role for in cell fate specification and differentiation of ventromedial -specific neurons. Last, does not have cross-inhibitory effects on , , and These findings are the first to reveal a role for in hypothalamic development.
结节下丘脑由背内侧核、腹内侧核和弓状核以及部分外侧下丘脑区域组成，它控制着广泛的生理机能。在神经发生过程中，结节下丘脑神经元被认为是从背侧向腹侧和从外向内产生的，尽管多年来人们对这种描述的准确性提出了质疑。此外，控制该区域神经发生时间的内在因素还没有很好地描述。神经前体细胞基因，包括 （）和 （），在下丘脑前体细胞中广泛表达，并有助于谱系决定和特定于亚型的神经元鉴定，但神经基因 2（Neurog2）的潜在作用仍未得到探索。雌雄小鼠的出生标记显示，结节下丘脑神经发生早在 E9.5 时就在外侧下丘脑和弓状核开始，并迅速扩展到 E10.5 时的背内侧和腹内侧神经元，E11.5 时在整个区域达到高峰。我们证实了一种从外向内的趋势，但 E9.5 出生的神经元除外，并揭示了一个头侧到尾侧的进展，但没有确认结节下丘脑神经元出生的背侧到腹侧模式。在 （）缺失的情况下，神经发生停滞，早期 BrdU 细胞数量显著减少，但在后期没有变化。此外， （）的缺失也导致神经元出生延迟，这表明 （）不能拯救 （）的缺失，并且这些神经前体细胞基因在结节下丘脑独立发挥作用。总之，我们的研究结果表明， （）作为一种经典的神经前体细胞基因，调节结节下丘脑神经发生的时间进程。在这里，我们研究了结节下丘脑内神经发生的一般时间和模式。我们的结果证实了神经发生的从外向内的趋势，并揭示了一个头侧到尾侧的进展。我们还表明， （）作为一种经典的神经前体细胞基因，负责调节腹内侧下丘脑早期出生神经元的出生，独立于 （）此外，我们揭示了 （）在腹内侧特定神经元的细胞命运特化和分化中的作用。最后， （）对 （）、 （）和 （）没有交叉抑制作用。这些发现首次揭示了 （）在下丘脑发育中的作用。
