Abstract
Cilia are evolutionarily conserved hair-like structures with a wide spectrum of key biological roles, and their dysfunction has been linked to a growing class of genetic disorders, known collectively as ciliopathies. Many strides have been made towards deciphering the molecular causes for these diseases, which have in turn expanded the understanding of cilia and their functional roles. One recently-identified ciliary gene is ARL2BP, encoding the ADP-Ribosylation Factor Like 2 Binding Protein. In this study, we have identified multiple ciliopathy phenotypes associated with mutations in ARL2BP in human patients and in a mouse knockout model. Our research demonstrates that spermiogenesis is impaired, resulting in abnormally shaped heads, shortened and mis-assembled sperm tails, as well as in loss of axonemal doublets. Additional phenotypes in the mouse included enlarged ventricles of the brain and situs inversus. Mouse embryonic fibroblasts derived from knockout animals revealed delayed depolymerization of primary cilia. Our results suggest that ARL2BP is required for the structural maintenance of cilia as well as of the sperm flagellum, and that its deficiency leads to syndromic ciliopathy.
Highlights
Cilia are short, protruding organelles often referred to as “signaling hubs”
Concurrent with the identification of the male patient, we discovered that male Arl2bp KO mice were infertile, as they were not yielding any litters during the generation of the murine Arl2bp KO model to study blindness [16]
We show that additional cilia-related phenotypes originate from the loss of full- length ADP-Ribosylation Factor Like 2 Binding Protein (ARL2BP), which point to the need for ARL2BP in cilia and flagella structure and maintenance
Summary
Cilia are short, protruding organelles often referred to as “signaling hubs”. These microtubulebased structures are involved in diverse functional roles, and impairment of their structure or function often leads to a class of genetic diseases known as “ciliopathies” [1]. Cilia contain a highly organized structure, consisting of a 9+0 (motile and immotile) or a 9+2 (motile) microtubule arrangement, starting with triplet tubules at their base (basal body and transition zone), doublet tubules throughout the axoneme, and singlets at their tip [2, 3]. The sperm flagellum is the longest in the body (~100μm in mice) and possesses additional accessory structures not present in other cilia (illustrated in S2 Fig), including the transient microtubular-based structure, the manchette, which assists in axoneme growth [6]
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