Abstract：
The Microphthalmia-associated Transcription Factor (MITF) governs numerous cellular and developmental processes. In mice, it promotes specification and differentiation of the retinal pigmented epithelium (RPE), and in humans, some mutations in MITF induce congenital eye malformations. Herein, we explore the function and regulation of Mitf in Drosophila eye development and uncover two roles. We find that knockdown of Mitf results in retinal displacement (RDis), a phenotype associated with abnormal eye formation. Mitf functions in the peripodial epithelium (PE), a retinal support tissue akin to the RPE, to suppress RDis, via the Hippo pathway effector Yorkie (Yki). Yki physically interacts with Mitf and can modify its transcriptional activity in vitro. Severe loss of Mitf, instead, results in the de-repression of retinogenesis in the PE, precluding its development. This activity of Mitf requires the protein phosphatase 2 A holoenzyme STRIPAK-PP2A, but not Yki; Mitf transcriptional activity is potentiated by STRIPAK-PP2A in vitro and in vivo. Knockdown of STRIPAK-PP2A results in cytoplasmic retention of Mitf in vivo and in its decreased stability in vitro, highlighting two potential mechanisms for the control of Mitf function by STRIPAK-PP2A. Thus, Mitf functions in a context-dependent manner as a key determinant of form and fate in the Drosophila eye progenitor epithelium.
摘要：
小眼症相关转录因子（MITF）控制着许多细胞和发育过程。在老鼠身上,它促进视网膜色素上皮（RPE）的规范和分化，而在人类中,MITF中的一些突变会导致先天性眼畸形。在这里，我们探讨了Mitf在果蝇眼发育中的功能和调节，并揭示了两种作用。我们发现击倒Mitf会导致视网膜位移（RDis），与异常眼形成相关的表型。线粒体在周围上皮（PE）中的功能，类似于RPE的视网膜支撑组织，为了抑制RDis，通过河马途径效应约基（Yki）。Yki与Mitf物理相互作用，并可以在体外修饰其转录活性。严重失去了Mitf,相反，导致PE中视网膜生成的去抑制，阻止其发展。Mitf的这种活性需要蛋白磷酸酶2A全酶STRIPAK-PP2A，而不是Yki；STRIPAK-PP2A在体外和体内增强了Mitf的转录活性。敲除STRIPAK-PP2A导致体内Mitf的细胞质保留和体外稳定性降低。强调了STRIPAK-PP2A控制Mitf功能的两种潜在机制。因此，Mitf在果蝇眼祖细胞上皮中作为形式和命运的关键决定因素以上下文依赖的方式起作用。
