Tmem138, a photoreceptor connecting cilium (CC) protein, is required for rhodopsin transport across the cilium and outer segment (OS) biogenesis

作者：Dianlei Guo, Jiali Ru, Lijing Xie, Mingjuan Wu, Yingchun Su, Shi‐Yong Zhu, Shujuan Xu, Yanhong Wei, Xialin Liu, Yizhi Liu, Chunqiao Liu · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2021 · DOI：10.1101/2021.05.22.445289 · 被引用次数：1 · 研究领域：Genetic and Kidney Cyst Diseases、Retinal Development and Disorders、Biomedical Research and Pathophysiology

Abstract Photoreceptor connecting cilium (CC) is structurally analogous to the transition zone (TZ) of primary cilia and gates the molecular trafficking between the inner and the outer segment (OS). Retinal dystrophies with underlying CC defects are manifested in a broad array of syndromic conditions known as ciliopathies as well as non-syndromic retinal degenerations. Despite extensive studies, protein trafficking across the photoreceptor CC is largely unknown. Here we genetically inactivated mouse Tmem138 , a gene encoding a ciliary membrane protein localized to the ciliary TZ and linked to Joubert syndrome (JBTS). Germline deletion of Tmem138 abolished OS morphogenesis followed by rapid photoreceptor degeneration. Tmem138 was found localized to the photoreceptor CC and, accordingly, the molecular compartments of the CC and axoneme of the mutant photoreceptors were altered despite ciliogenesis proceeding normally at the early stage of photoreceptor development. To gain further insights into Tmem138 function in OS biogenesis, we focused on trafficking of rhodopsin, the most abundant protein of the OS. Mislocalization of rhodopsin was readily observed as early as P5 in the mutant photoreceptors prior to growth of the OS. Ablation of Tmem138 in mature rods recapitulated the molecular changes in the germline mutants, causing well-formed outer segment discs to disintegrate accompanied by mislocalization of rhodopsin in the cell body. Furthermore, Tmem138 interacted with rhodopsi...