Title | Foxp1 suppresses cortical angiogenesis and attenuates HIF-1alpha signaling to promote neural progenitor cell maintenance. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Buth, JE, Dyevich, CE, Rubin, A, Wang, C, Gao, L, Marks, T, Harrison, MRm, Kong, JH, M Ross, E, Novitch, BG, Pearson, CAlayne |
Journal | EMBO Rep |
Volume | 25 |
Issue | 5 |
Pagination | 2202-2219 |
Date Published | 2024 May |
ISSN | 1469-3178 |
Keywords | Angiogenesis, Animals, Cell Differentiation, Cerebral Cortex, Forkhead Transcription Factors, Glycolysis, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Neovascularization, Physiologic, Neural Stem Cells, Neurogenesis, Repressor Proteins, Signal Transduction, Vascular Endothelial Growth Factor A |
Abstract | Neural progenitor cells within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions later. Yet, the mechanisms controlling this transition remain unclear. Previous work has shown that early but not late neural progenitor cells (NPCs) endogenously express the autism-linked transcription factor Foxp1, and both loss and gain of Foxp1 function can alter NPC activity and fate choices. Here, we show that premature loss of Foxp1 upregulates transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with a premature destabilization of HIF-1α, an elevation in HIF-1α target genes, including Vegfa in NPCs, and precocious vascular network development. In vitro experiments demonstrate that stabilization of HIF-1α in Foxp1-deficient NPCs rescues the premature differentiation phenotype and restores NPC maintenance. Our data indicate that the endogenous decline in Foxp1 expression activates the HIF-1α transcriptional program leading to changes in the tissue environment adjacent to NPCs, which, in turn, might alter their self-renewal and neurogenic capacities. |
DOI | 10.1038/s44319-024-00131-8 |
Alternate Journal | EMBO Rep |
PubMed ID | 38600346 |
PubMed Central ID | PMC11094073 |
Grant List | R00GM132518 / GF / NIH HHS / United States R01 NS105477 / NS / NINDS NIH HHS / United States AHA941434 / / American Heart Association (AHA) / R01NS105477 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / R00 GM132518 / GM / NIGMS NIH HHS / United States TG2-01169 / / California Institute for Regenerative Medicine (CIRM) / P30NS062691 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / P30CA015704 / / NIH/NCI / R01NS126209 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / R01 NS089817 / NS / NINDS NIH HHS / United States U54HD087101 / / HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) / EDUC4-12753 / / Rose Hills Foundation (RHF) / P30 CA015704 / CA / NCI NIH HHS / United States P50HD103557 / / HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) / P50 HD103557 / HD / NICHD NIH HHS / United States U54 HD087101 / HD / NICHD NIH HHS / United States U54 NS117170 / NS / NINDS NIH HHS / United States R01 NS126209 / NS / NINDS NIH HHS / United States R01NS089817 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / P30 NS062691 / NS / NINDS NIH HHS / United States |