Oxygen-Tension and the VHL-Hif1α Pathway Comprise a Developmental Switch Controlling the Onset of Neuronal Polarization and Germinal Zone Exit

Abstract

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. Despite studies implicating cell polarity as an intrinsic organizer of morphogenetic events, the nature of cues instructing neuron polarization and their coupling during postnatal development is unclear. We found a link between oxygen tension, which rises after birth, the von Hippel– Lindau(VHL)–hypoxia-inducible factor 1α (Hif1α) pathway, and the polarization regulating the maturation of post-mitotic cerebellar granule neurons (CGNs). At postnatal stages with low GZ vascularization, Hif1α modulates CGN-progenitor cell-cycle exit. Unexpectedly, the VHL-Hif1α pathway also delays the timing of CGN differentiation, germinal zone exit, and migration initiation by regulating newborn neuron niche interactions via transcriptional repression of the partitioning-defective(Pard) complex. As vascularization proceeds, these inhibitory mechanisms recede, implicating oxygen fluctuation as a developmental switch regulating neuronal polarization and a key shaper of the nascent steps of circuit formation.