title: The Meckel syndrome- associated protein MKS1 functionally interacts with components of the BBSome and IFT complexes to mediate ciliary trafficking and hedgehog signaling.
abstract: The importance of primary cilia in human health is underscored by the link between ciliary dysfunction and a group of primarily recessive genetic disorders with overlapping clinical features, now known as ciliopathies. Many of the proteins encoded by ciliopathy-associated genes are components of a handful of multi-protein complexes important for the transport of cargo to the basal body and/or into the cilium. A key question is whether different complexes cooperate in cilia formation, and whether they participate in cilium assembly in conjunction with intraflagellar transport (IFT) proteins. To examine how ciliopathy protein complexes might function together, we have analyzed double mutants of an allele of the Meckel syndrome (MKS) complex protein MKS1 and the BBSome protein BBS4. We find that Mks1; Bbs4 double mutant mouse embryos exhibit exacerbated defects in Hedgehog (Hh) dependent patterning compared to either single mutant, and die by E14.5. Cells from double mutant embryos exhibit a defect in the trafficking of ARL13B, a ciliary membrane protein, resulting in disrupted ciliary structure and signaling. We also examined the relationship between the MKS complex and IFT proteins by analyzing double mutant between Mks1 and a hypomorphic allele of the IFTB component Ift172. Despite each single mutant surviving until around birth, Mks1; Ift172avc1 double mutants die at mid-gestation, and exhibit a dramatic failure of cilia formation. We also find that Mks1 interacts genetically with an allele of Dync2h1, the IFT retrograde motor. Thus, we have demonstrated that the MKS transition zone complex cooperates with the BBSome to mediate trafficking of specific trans-membrane receptors to the cilium. Moreover, the genetic interaction of Mks1 with components of IFT machinery suggests that the transition zone complex facilitates IFT to promote cilium assembly and structure.
authors.affiliation: Program in Developmental Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Ave. New York, United States of America.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Sarah C
authors.identifier: http://orcid.org/0000-0001-9705-6390
authors.initials: SC
authors.lastname: Goetz
authors.affiliation: Program in Developmental Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Ave. New York, United States of America.
authors.forename: Fiona
authors.identifier: http://orcid.org/0000-0003-0297-8558
authors.initials: F
authors.lastname: Bangs
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Chloe L
authors.initials: CL
authors.lastname: Barrington
authors.affiliation: Department of Cell Biology and Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Program in Developmental Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Ave. New York, United States of America.
authors.forename: Kathryn V
authors.identifier: http://orcid.org/0000-0003-1657-2161
authors.initials: KV
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D002925:Ciliary Motility Disorders / Q000378:metabolism*; D004677:Encephalocele / Q000378:metabolism*; D005407:Flagella / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D007690:Polycystic Kidney Diseases / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D012174:Retinitis Pigmentosa
chemical_list: C506281:BBS4 protein, mouse; D053823:Hedgehog Proteins; C509166:MKS1 protein, mouse; D008869:Microtubule-Associated Proteins; D011506:Proteins