The role of hypoxia and HIF-2 in sympathoadrenal development

Hypoxia-inducible factors (HIF-1/HIF-2) are oxygen-regulated transcription factors with widespread roles in adaptive physiology. HIFs also have roles in development that are less well understood but could provide a mechanism for observations that developmental hypoxia programmes adult cardiovascular dysfunction. HIF-2 is of particular interest, given that HIF-2-activating mutations (pseudohypoxia) drive chromaffin cell tumours (pheochromocytoma/paraganglioma: PPGL). HIF-2 expression in PPGLs is associated with downregulation of PNMT, which catalyses adrenaline biosynthesis and labels differentiated chromaffin cells.

My work on pseudohypoxic mice links loss of PNMT+ chromaffin cells to expansion of cells overexpressing HIF-2, which are disorganised in peri-adrenal locations, suggesting impaired migration and differentiation of sympathoadrenal precursors. Here, I will exploit sympathoadrenal development as a paradigm for understanding how hypoxia controls development, the embryonic stages most susceptible, and the HIF-2-dependent component. I will use chicken embryos and sympathoadrenal differentiation of human iPS cells as complementary models of development that allow hypoxic, pharmacological and genetic interventions activating HIF-2, without confounding effects of materno-placental physiology, and provide the potential to follow effects on adult chickens.

These tractable approaches will allow me to determine how and when hypoxia affects proliferation, migration and differentiation of chromaffin precursors, and how hypoxia/HIF-2 impacts adult physiology to programme cardiovascular disease.