Integration of CNS survival and differentiation by HIF2α

Abstract

Hypoxia-inducible factor (HIF) 1α and HIF2α and the inhibitor of apoptosis survivin represent prominent markers of many human cancers. They are also widely expressed in various embryonic tissues, including the central nervous system; however, little is known about their functions in embryos. Here, we show that zebrafish HIF2α protects neural progenitor cells and neural differentiation processes by upregulating the survivin orthologues birc5a and birc5b during embryogenesis. Morpholino-mediated knockdown of hif2α reduced the transcription of birc5a and birc5b, induced p53-independent apoptosis and abrogated neural cell differentiation. Depletion of birc5a and birc5b recaptured the neural development defects that were observed in the hif2α morphants. The phenotypes induced by HIF2α depletion were largely rescued by ectopic birc5a and birc5b mRNAs, indicating that Birc5a and Birc5b act downstream of HIF2α. Chromatin immunoprecipitation assay revealed that HIF2α binds to birc5a and birc5b promoters directly to modulate their transcriptions. Knockdown of hif2α, birc5a or birc5b reduced the expression of the cdk inhibitors p27/cdkn1b and p57/cdkn1c and increased ccnd1/cyclin D1 transcription in the surviving neural progenitor cells. The reduction in elavl3/HuC expression and enhanced pcna, nestin, ascl1b and sox3 expression indicate that the surviving neural progenitor cells in hif2α morphants maintain a high proliferation rate without terminally differentiating. We propose that a subset of developmental defects attributed to HIF2α depletion is due in part to the loss of survivin activity.

Knockdown of Cyclin-dependent Kinase 10 (cdk10) Gene Impairs Neural Progenitor Survival via Modulation of raf1a Gene Expression

“…This phenomenon of cell death may result in compensatory proliferation, thereby influencing cell cycle distribution and abrogation of differentiation. This finding is consistent with the results of previous studies on Drosophila (24), chicken (25), and zebrafish embryos (26). We then performed in vitro and in vivo assays to assess cell cycle progression using gain and loss of cdk10 function.…”

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

“…S6 A and C) implies that in pediatric tumors the role of HIF2α is different from its role in adult tumors. Interestingly, studies show that during development HIF2α is necessary for differentiation of neural crest-derived catecholamineproducing cells in mice (52) and for neural differentiation in the vertebrate CNS (53). During development, the proto-oncogene MYCN regulates expansion and ventral migration of neural crest cells, but levels decline as cells undergo sympathoadrenal differentiation (54).…”

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

“…Most reports studying VHL/HIF transcriptional activation have focused on HIF-bound promoters (23)(24)(25)(26)(27)(28). However, recent evidence suggests an emerging role for distal enhancer elements in VHL/HIF transcriptional control ( 29,30 ).…”