Function of HIF2α on retina development

• Main Authors: Po-Han Lee, 李柏翰
• Other Authors: Chin-Hwa Hu
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/17780859283792283503

碩士 === 國立臺灣海洋大學 === 生物科技研究所 === 98 === Hypoxia-inducible factors (HIFs) are known for their functions in oxygen homeostasis by regulating the genes for glucose uptake and metabolism, erythorpoiesis, angiogenesis, apoptosis and cell proliferation. The HIFs are heterodimeric basic-helix-loop-helix-PAS transcription factors consisting of an oxygen-sensitive alpha subunit and a constitutively expressed beta subunit, also known as ARNT. When cells are subjected to hypoxia, the HIFα factors are stabilized, associate with ARNT and activate the target genes. Previously it was revealed that concurrent knockdown of zebrafish hif1α, -2α and -3α inhibited the bipolar cell marker vsx1 and photoreceptor marker rho transcriptions, indicating that the retinal development was abrogated in hif1α/-2α/-3α morphants. Further investigation revealed that the retinal defects occurred hif1α/-2α/-3α morphant embryos was caused by the action of hif2α antisense morpholino. Knockdown of hif2α eliminated rho expression. There are multiple hypoxia-responsible elements in the upstream promoter regions of rho gene. It raises a possibility that rho transcription is controlled by HIF2 directly. Nevertheless, mutating the HRE sequence in the 2.4 kb of rho promoter fragment did not eliminate the promoter activity, indicating that rho is not controlled directly by HIF2-interaction. It was shown that the differentiation of neural progenitor cells in zebrafish CNS is controlled by HIF2α by means of transcriptional regulation of survivin orthologues Birc5a and Birc5b during embryonic stages. The function of survivin orthologues in retina development is investigated by reverse genetic studies. Knock down of survivin-1/birc5a or survivin-2/birc5b all results in inhibition of rho transcription, suggesting that survivin genes act critical functions in retina development. In hif2α or survivin-1/birc5a morphant embryos, only the transcriptions of mid- and late-stage markers (including huC, neuroD ,vsx1 and rho),but not early stage markers (such as rx1), were affected, indicating hif2α and its downstream target birc5a functions on mid-stages of retina development. In conclusion, this study suggests that HIF2α controls retina development indirectly through its downstream survivin/birc5 genes, but it does not control rho transcription directly.