Hif1α-dependent hypoxia signaling contributes to the survival of deep-layer neurons and cortex formation in a mouse model

Abstract

Hypoxia-inducible factor 1 α (Hif1α) plays a crucial role in brain development. To study the function of Hif1α in early brain development, we generated neuroepithelial cell-specific Hif1α-knockout mice. Hif1α-knockout mice died soon after birth; these mice exhibited an abnormal head shape, indicating the presence of brain defects. Morphological analysis revealed that Hif1α ablation reduced the overall size of the brain, especially affecting the telencephalon. Neuronal apoptosis predominantly occurred in deep-layer neurons, consequently the alignment of cortical layers was severely disorganized in Hif1α knockout mice. Furthermore, we demonstrated that Vegf signaling contributes to the survival of deep-layer neurons as a downstream effector of Hif1α-dependent hypoxia signaling. Taken together, our findings demonstrate that Hif1α plays a critical role in the early stages of telencephalon development.

From Vessels to Neurons—The Role of Hypoxia Pathway Proteins in Embryonic Neurogenesis

“…In contrast, the positioning of neurons was regulated cell autonomously as HIF-1α KO neurons localized more apically suggesting impaired migration. However, the authors did not observe any major effect on proliferation or NPC numbers, possibly due to the length of time between onset of HIF deletion and analysis [163].…”

“…Neurites of newly born migrating neurons also preferentially align with blood vessels [146], which have been shown to guide the migratory pattern of ventrally born interneurons destined for the neocortex [159][160][161][162]. Collectively, changes to cortical angiogenesis patterns during neurogenesis influence neuron and glia production as well as neuronal survival eventually resulting in altered cortical thickness [148,155,163]. The effects of vasculature are not limited to direct cell-cell contacts or oxygenation, as they also encompass the delivery of other signaling molecules and nutrients.…”

“…However, the early effects of HIF-1α deletion on NPCs could have been missed due to low efficiency of nestin-Cre mediated recombination before E17.5 [147,189]. To overcome this limitation, Sakai and others [163] deleted HIF-1α in NECs using Sox1-cre mouse line, in which Cre recombinase is expressed in the neuroepithelium as early as E8.5. This resulted in early postnatal lethality, abnormal head shape and brain defects, particularly reduced telencephalon size visible from E14.5.…”

Glycolytic activity is required for the onset of neural plate folding during neural tube closure in mouse embryos

“…We analyzed gene expression using RT-qPCR as described ( Sakai et al, 2022 ). Briefly, total RNA extracted from E8.5 (9–11 somite stage) embryos was reverse-transcribed into cDNA, which was then amplified by qPCR using SYBR Green on a LightCycler Nano System (Roche).…”

Toward an understanding of glucose metabolism in radial glial biology and brain development

“…Genetic manipulations in mouse embryos shed some light on the contribution of oxygen levels and HIF1α signaling in RG at mid-neurogenic stages ( Table 1 ). Conditional removal of both HIF1α alleles in mouse RG severely impacts cortical angiogenesis, resulting in hypoplasia, microcephaly, and neuronal cell death ( Tomita et al, 2003 ; Lange et al, 2016 ; Sakai et al, 2022 ). Removing one HIF1α allele is sufficient to rescue the angiogenesis phenotype and allow investigation of the role of HIF1α signaling in RG ( Lange et al, 2016 ; Komabayashi-Suzuki et al, 2019 ).…”