RESUMO
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.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Sistema Nervoso Central/citologia , Proteínas de Peixe-Zebra/metabolismo , Animais , Apoptose , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Embrião não Mamífero , Desenvolvimento Embrionário , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Morfolinos/farmacologia , Regiões Promotoras Genéticas , Ligação Proteica , Células-Tronco/citologia , Survivina , Regulação para Cima , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genéticaRESUMO
New planar GaAs heterojunction bipolar phototransistors have been designed and demonstrated. The devices use a GaAs/Al(0.3)Ga(0.7) As molecular-beam-epitaxy materials system with an Al(0.3)Ga(0.7) As passivated, 10-nm-thick base; a depleted, high-low emitter; and a low emitter-base capacitance. Electrical contact to the emitter is made by a set of parallel, ohmic fingers and to the collector by an ohmic contact formed in a large, approximately 1.48-microm deep via. Rise times in response to impulse optical excitation at 810 nm were 747-891 ps except at the two lowest optical excitation powers measured. Photocurrent gains measured at 810 and 850 nm were 0.67-19, depending on experimental conditions. These devices are promising for use in heterodyne photodetector arrays for coherent optical processing channelizers requiring a 100-MHz bandwidth.
