KIF11 Inhibition Induces Retinopathy Progression by Affecting Photoreceptor Cell Ciliogenesis and Cell Cycle Regulation in Development.

Abstract

Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR; OMIM 152950) is a rare autosomal dominant disorder, which is primarily characterized by defects in the central nervous system and retinal developmental anomalies. Kinesin-5 KIF11 has been discovered as a major causative gene for MCLMR. It has been well established that KIF11 is essential for microtubule organization, centrosome separation, and spindle assembly during mitosis. However, cellular and molecular mechanisms in the physiopathology of MCLMR remain largely unknown. In this study, KIF11-inhibition mouse models are generated, which reveal that chemical inhibition of KIF11 results in defects in retinal development, the formation of rosettes, photoreceptor ciliary alterations, and vision loss. Furthermore, it is demonstrated that KIF11 is essential for the formation, organization, and maintenance of primary cilia in photoreceptor cells, which further contributes to the organization of photoreceptor cells and the development of the retina. Using the developing mouse embryos as a model, it is revealed that KIF11 inhibition induces the formation of monopolar spindle and mitotic arrest, which further results in tetraploidy and apoptotic cell death. These findings uncover cellular mechanisms underlying the loss-of-function of KIF11 and retinopathy in MCLMR and further support the functions of KIF11 in development.