HIF1α controls somitogenesis and spine development by regulating levels of intracellular oxygen in the presomitic mesoderm

Abstract

Embryonic axis extension depends on presomitic mesoderm (PSM) segmentation into somites, which give rise to vertebrae and muscles. The PSM is a highly glycolytic structure. HIF1 is a transcription factor that regulates bioenergetic metabolism by promoting glycolysis and suppressing mitochondrial respiration. Conditional deletion of HIF1 in the PSM resulted in vertebral malformations, including shortened, misshapen vertebrae and additional thoracic segments. These defects correlated with disrupted segmentation clock oscillations, marked by abnormal Hes7 and Lfng expression. HIF1 loss also induced intracellular hypoxia, likely due to increased mitochondrial respiration. Hyperoxic exposure of mutant embryos corrected hypoxia, restoring Hes7 oscillations and somitogenesis. These findings highlight HIF1s essential role in ensuring proper segmentation clock function and somitogenesis by maintaining intracellular oxygen homeostasis through reprogramming of metabolism.