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- Title
Deletion of CEP164 in mouse photoreceptors post-ciliogenesis interrupts ciliary intraflagellar transport (IFT).
- Authors
Reed, Michelle; Takemaru, Ken-Ichi; Ying, Guoxin; Frederick, Jeanne M.; Baehr, Wolfgang
- Abstract
Centrosomal protein of 164 kDa (CEP164) is located at distal appendages of primary cilia and is necessary for basal body (BB) docking to the apical membrane. To investigate the function of photoreceptor CEP164 before and after BB docking, we deleted CEP164 during retina embryonic development (Six3Cre), in postnatal rod photoreceptors (iCre75) and in mature retina using tamoxifen induction (Prom1-ETCre). BBs dock to the cell cortex during postnatal day 6 (P6) to extend a connecting cilium (CC) and an axoneme. P6 retina-specific knockouts (retCep164-/-) are unable to dock BBs, thereby preventing formation of CC or outer segments (OSs). In rod-specific knockouts (rodCep164-/-), Cre expression starts after P7 and CC/OS form. P16 rodCep164-/- rods have nearly normal OS lengths, and maintain OS attachment through P21 despite loss of CEP164. Intraflagellar transport components (IFT88, IFT57 and IFT140) were reduced at P16 rodCep164-/- BBs and CC tips and nearly absent at P21, indicating impaired intraflagellar transport. Nascent OS discs, labeled with a fluorescent dye on P14 and P18 and harvested on P19, showed continued rodCep164-/- disc morphogenesis but absence of P14 discs mid-distally, indicating OS instability. Tamoxifen induction with PROM1ETCre;Cep164F/F (tamCep164-/-) adult mice affected maintenance of both rod and cone OSs. The results suggest that CEP164 is key towards recruitment and stabilization of IFT-B particles at the BB/CC. IFT impairment may be the main driver of ciliary malfunction observed with hypomorphic CEP164 mutations. Author summary: CEP164 is indispensable for docking of basal bodies to apical plasma membranes and formation of primary cilia. Homozygous truncations of CEP164 are associated with severe ciliopathy whereas missense mutations generate milder forms of nephronophthisis (NPHP). Recessive mutations of CEP164 are associated with NPHP, Meckel-Gruber (MKS) and Bardet-Biedl syndromes (BBS) in which primary cilia fail to form, or do not function correctly. We found that deletion of CEP164 in mouse photoreceptors before docking of the basal body (BB) to the apical inner segment membrane prevents elaboration of connecting cilia (CC, equivalent to transition zones) and outer segments (OSs, modified primary cilia). We also generated mouse models in which deletion of CEP164 occurs after OSs are established and observed that the BB/CC and axoneme are initially stable in the absence of CEP164. However, prolonged loss of CEP164 resulted in diminished recruitment of intraflagellar transport (IFT) proteins to the BB/CC, thereby affecting IFT which is required for maintenance of cilia and OSs. We propose that, in ciliopathies caused by CEP164 missense mutations (e.g., X1460WextX57 associated with Leber congenital amaurosis or LCA), impairment of IFT provides a mechanism for ciliary dysfunction and disease.
- Subjects
CILIA &; ciliary motion; PHOTORECEPTORS; CELL membranes; MISSENSE mutation; LAURENCE-Moon-Biedl syndrome; FLUORESCENT dyes
- Publication
PLoS Genetics, 2022, Vol 18, Issue 9, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1010154