Integration of CNS survival and differentiation by HIF2?.

ABSTRACT: Hypoxia-inducible factor (HIF) 1? and HIF2? 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 HIF2? protects neural progenitor cells and neural differentiation processes by upregulating the survivin orthologues birc5a and birc5b during embryogenesis. Morpholino-mediated knockdown of hif2? 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 hif2? morphants. The phenotypes induced by HIF2? depletion were largely rescued by ectopic birc5a and birc5b mRNAs, indicating that Birc5a and Birc5b act downstream of HIF2?. Chromatin immunoprecipitation assay revealed that HIF2? binds to birc5a and birc5b promoters directly to modulate their transcriptions. Knockdown of hif2?, 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 hif2? morphants maintain a high proliferation rate without terminally differentiating. We propose that a subset of developmental defects attributed to HIF2? depletion is due in part to the loss of survivin activity.

SUBMITTER: Ko CY 

PROVIDER: S-EPMC3190110 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature