Analysis of molecular mechanisms underlying retinal photoreceptor cell fate determination

在脊椎动物视网膜发育中，已知有六种类型的神经元和神经胶质细胞(光感受器、水平细胞、双极细胞、无长突细胞、神经节细胞和Müler神经胶质细胞)是由普通的多能前体细胞产生的。在这个发育过程中，控制视网膜发育的基因表达程序需要通过激活适当基因的表达和抑制不适当基因的表达来进行精确调控。我们利用小鼠分子遗传学分析了这种遗传程序背后的分子机制。在本项目中，我们阐明了决定细胞命运、表观遗传调控、光感受器成熟和存活的几个重要机制。此外，我们开发了用腺病毒相关病毒(AAV)进行基因治疗的系统，这是基因治疗适用于人类视网膜发育障碍和退化的重要线索。

In vertebrate retinal development, it has been known that six types of neurons and glial cells (photoreceptors, horizontal cells, bipolar cells, amacrine cells, ganglion cells, and Müller glial cells) are generated from common multipotent progenitor cells. In this developmental process, the gene expression programs controlling retinal development need to be precisely regulated by activating the expression of proper genes and repressing the expression of improper genes. We analyzed the molecular mechanisms underlying this genetic program using mouse molecular genetics. In the current project, we clarified several important mechanisms in cell fate determination, epigenetic regulation, maturation, and survival of photoreceptors. In addition, we developed a gene therapy system using AAV (adenovirus-associated virus), which is a important clue to the suitability of gene therapy for developmental disorders and degeneration of the retina in humans.