Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Molecular Neurobiology Group, Institute of Physiological Chemistry, Philipps University of Marburg, 35032 Marburg, Germany.
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Neuron. 2020 May 20;106(4):607-623.e5. doi: 10.1016/j.neuron.2020.02.025. Epub 2020 Mar 16.
Postnatal brain circuit assembly is driven by temporally regulated intrinsic and cell-extrinsic cues that organize neurogenesis, migration, and axo-dendritic specification in post-mitotic neurons. While cell polarity is an intrinsic organizer of morphogenic events, environmental cues in the germinal zone (GZ) instructing neuron polarization and their coupling during postnatal development are unclear. We report that oxygen tension, which rises at birth, and the von Hippel-Lindau (VHL)-hypoxia-inducible factor 1α (Hif1α) pathway regulate polarization and maturation of post-mitotic cerebellar granule neurons (CGNs). At early postnatal stages with low GZ vascularization, Hif1α restrains CGN-progenitor cell-cycle exit. Unexpectedly, cell-intrinsic VHL-Hif1α pathway activation also delays the timing of CGN differentiation, germinal zone exit, and migration initiation through transcriptional repression of the partitioning-defective (Pard) complex. As vascularization proceeds, these inhibitory mechanisms are downregulated, implicating increasing oxygen tension as a critical switch for neuronal polarization and cerebellar GZ exit.
出生后大脑回路的组装是由时间调节的内在和细胞外在的线索驱动的，这些线索组织了神经发生、迁移和有丝分裂后神经元的轴突-树突特化。虽然细胞极性是形态发生事件的内在组织者，但指导神经元极化及其在出生后发育过程中偶联的生发区（GZ）中的环境线索尚不清楚。我们报告说，出生时升高的氧张力和 von Hippel-Lindau（VHL）-缺氧诱导因子 1α（Hif1α）途径调节着出生后小脑颗粒神经元（CGN）的极化和成熟。在早期的具有低 GZ 血管化的新生阶段，Hif1α 抑制 CGN-祖细胞细胞周期退出。出乎意料的是，细胞内在的 VHL-Hif1α 途径的激活也通过对分区缺陷（Pard）复合物的转录抑制来延迟 CGN 分化、生发区退出和迁移起始的时间。随着血管化的进行，这些抑制机制被下调，表明氧张力的增加是神经元极化和小脑 GZ 退出的关键开关。
