Neuron
Volume 106, Issue 4, 20 May 2020, Pages 607-623.e5
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Article
Oxygen Tension and the VHL-Hif1α Pathway Determine Onset of Neuronal Polarization and Cerebellar Germinal Zone Exit

https://doi.org/10.1016/j.neuron.2020.02.025Get rights and content
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Highlights

  • An extended postnatal phase of cerebellar hypoxia aids GNP proliferation via Hif1α

  • Hif1α controls CGN GZ exit and Pard complex function by activating Zeb1 expression

  • Hif1α-Zeb1 antagonism of Pard6α modulates Itgβ1 adhesion that promotes GZ occupancy

  • Hif1α control of polarity is a basis to dissect the pathology of hypoxic insults

Summary

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.

Keywords

vascularization
neuronal differentiation
cell polarity
Pard Complex
Hif1 Pathway
Zeb1
Integrin

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