Phosphatidylinositol 4,5-bisphosphate regulates cilium transition zone maturation in Drosophila melanogaster

Abstract

Cilia are cellular antennae that are essential for human development and physiology. A large number of genetic disorders linked to cilium dysfunction are associated with proteins that localize to the ciliary transition zone (TZ), a structure at the base of cilia that regulates trafficking in and out of the cilium. Despite substantial effort to identify TZ proteins and their roles in cilium assembly and function, processes underlying maturation of TZs are not well understood. Here, we report a role for the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP) in TZ maturation in the male germline. We show that reduction of cellular PIP levels through ectopic expression of a phosphoinositide phosphatase or mutation of the type I phosphatidylinositol phosphate kinase Skittles induces formation of longer than normal TZs. These hyperelongated TZs exhibit functional defects, including loss of plasma membrane tethering. We also report that the () allele of decouples TZ hyperelongation from loss of cilium-plasma membrane tethering. Our results reveal a requirement for PIP in supporting ciliogenesis by promoting proper TZ maturation.

A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development

“…Secondly, Inpp5e could control Gli3 processing through its effect on the transition zone (TZ). It is required for TZ molecular organization ( Dyson et al, 2017 ) and its substrate PI(4,5)P2 plays a role in TZ maturation in Drosophila ( Gupta et al, 2018 ). This model is further supported by our finding that a mouse mutant for the TZ protein Tctn2 phenocopies the Inpp5e Δ/Δ neurogenesis defect.…”

The Caenorhabditis elegans Tubby homolog dynamically modulates olfactory cilia membrane morphogenesis and phospholipid composition

“…Altered PI(4,5)P 2 distribution at the PCMC in tub-1 mutants is expected to significantly affect both endo- and exocytosis as well as entry and exit of ciliary proteins (Grossman et al, 2011; Martin, 2012; Park et al, 2015; Posor et al, 2015; Wallroth and Haucke, 2018). PI(4,5)P 2 levels also alter multiple aspects of ciliogenesis including transition zone maturation (Gupta et al, 2018; Xu et al, 2016; Xu et al, 2019). However, since initial steps of ciliogenesis appear to be unaffected in tub-1 L1 larvae (see Figure 1B), we favor the hypothesis that TUB-1 regulates membrane biogenesis in AWB via regulation of vesicular trafficking at the cilia base and membrane transport within cilia.…”

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…Chloride channel defects resulted in similar progression, raising the possibility that chloride homeostasis is important for OS development. This idea is supported by evidence that chloride transport by the chloride channel ANO1 is required for ciliogenesis [508] and that control of intracellular chloride ion levels by this channel regulates the membrane organization of phosphatidylinositol 4,5-bisphosphate [509], a prominent lipid that regulates ciliary development [131,510]. Characterization of early OS development in mouse models defective in chloride channels CLCN2, CLCN3, or CLCN7 may provide mechanistic clues on the role of intracellular chloride in ciliogenesis.…”