Mutation of FOP/FGFR1OP in mice recapitulates human short rib-polydactyly ciliopathy

Abstract

Skeletal dysplasias are a clinically and genetically heterogeneous group of bone and cartilage disorders. A total of 436 skeletal dysplasias are listed in the 2015 revised version of the nosology and classification of genetic skeletal disorders, of which nearly 20% are still genetically and molecularly uncharacterized. We report the clinical and molecular characterization of a lethal skeletal dysplasia of the short-rib group caused by mutation of the mouse Fop gene. Fop encodes a centrosomal and centriolar satellite (CS) protein. We show that Fop mutation perturbs ciliogenesis in vivo and that this leads to the alteration of the Hedgehog signaling pathway. Fop mutation reduces CSs movements and affects pericentriolar material composition, which probably participates to the ciliogenesis defect. This study highlights the role of a centrosome and CSs protein producing phenotypes in mice that recapitulate a short rib-polydactyly syndrome when mutated.

Centrosomal and ciliary targeting of CCDC66 requires cooperative action of centriolar satellites, microtubules and molecular motors

“…However, these events were very infrequent, and the majority of satellites displayed short-range diffusive motility. Although previous studies described the bimodal motility for satellites qualitatively, the predominant diffusive behavior of satellites has not been reported 37,66,70 . This result has important implications for our understanding of satellite mechanisms.…”

“…There is heterogeneity in the composition of individual satellites, and CCDC66 localizes only to a subset of satellites 15,43,65 . To investigate whether the dynamics of CCDC66-positive satellites are representative of all satellites in cells, we performed time-lapse imaging experiments in HeLa Kyoto cells stably expressing GFP-PCM1 from a bacterial artificial chromosome (BAC) transgene, which was recently used to study the function of FGFR1 oncogene partner (FOP) on satellite dynamics 66,67 . Representative satellites and their trajectories are shown in Fig.…”

“…The trafficking model for centriolar satellites was based on directed motility reported for a subset of satellites and changes in the centrosomal levels of various proteins in satellite-less cells 28,37–39,66 . The lack of quantitative analysis of satellite dynamics in cells in an unbiased way has made this model incomplete.…”

FOP Negatively Regulates Ciliogenesis and Promotes Cell Cycle Re-entry by Facilitating Primary Cilia Disassembly

“…However, the roles of FOP in cilia assembly and disassembly are not fully understood. Although several recent studies have reported that near complete silencing of FOP inhibited primary cilia formation (Kanie et al, 2017;Mojarad et al, 2017;Cabaud et al, 2018), others found that moderate knockdown of FOP did not affect ciliogenesis (Graser et al, 2007;Lee and Stearns, 2013). Here we have demonstrated that FOP negatively regulates ciliogenesis based on the following evidence: firstly, the expression of FOP is inversely correlated with ciliogenesis.…”

“…FOP is a centrosomal and centriolar satellites protein and is involved in multiple biological processes, such as MT anchoring, ciliogenesis, cell cycle progression, and cancer development (Yan et al, 2006;Mano et al, 2007;Acquaviva et al, 2009;Lee and Stearns, 2013;Kanie et al, 2017;Mojarad et al, 2017;Cabaud et al, 2018). However, the roles of FOP in cilia assembly and disassembly are not fully understood.…”