A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition

Garcia-Gonzalo, Francesc R.; Corbit, Kevin C.; Sirerol-Piquer, María Salomé; Ramaswami, Gokul; Otto, Edgar A.; Noriega, Thomas R.; Seol, Allen D.; Robinson, Jon F.; Bennett, Christopher L.; Josifova, Dragana; García‐Verdugo, José Manuel; Katsanis, Nicholas; Hildebrandt, Friedhelm; Reiter, Jeremy F.

doi:10.1038/ng.891

Cited by 576 publications

(868 citation statements)

References 49 publications

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“…5A). We recently showed that different cell types have distinct genetic requirements for ciliogenesis, and it is possible that CA1 affects a cell type-specific aspect of ciliogenesis (39,40). Consistent with the inability of CA1 to inhibit ciliogenesis in ASZ1 and NIH 3T3 cells, CA1 also did not inhibit Hh pathway activity in these cells (Figs.…”

Section: Ca1 and Ca2 Inhibit Ciliogenesis Through Distinct Effects Onsupporting

confidence: 52%

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

Chen

Arkin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Vertebrate Hedgehog (Hh) signals involved in development and some forms of cancer, such as basal cell carcinoma, are transduced by the primary cilium, a microtubular projection found on many cells. A critical step in vertebrate Hh signal transduction is the regulated movement of Smoothened (Smo), a seven-transmembrane protein, to the primary cilium. To identify small molecules that interfere with either the ciliary localization of Smo or ciliogenesis, we undertook a high-throughput, microscopy-based screen for compounds that alter the ciliary localization of YFP-tagged Smo. This screen identified 10 compounds that inhibit Hh pathway activity. Nine of these Smo antagonists (SA1–9) bind Smo, and one (SA10) does not. We also identified two compounds that inhibit ciliary biogenesis, which block microtubule polymerization or alter centrosome composition. Differential labeling of cell surface and intracellular Smo pools indicates that SA1–7 and 10 specifically inhibit trafficking of intracellular Smo to cilia. In contrast, SA8 and 9 recruit endogenous Smo to the cilium in some cell types. Despite these different mechanisms of action, all of the SAs inhibit activation of the Hh pathway by an oncogenic form of Smo, and abrogate the proliferation of basal cell carcinoma-like cancer cells. The SA compounds may provide alternative means of inhibiting pathogenic Hh signaling, and our study reveals that different pools of Smo move into cilia through distinct mechanisms.

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Section: Ca1 and Ca2 Inhibit Ciliogenesis Through Distinct Effects Onsupporting

confidence: 52%

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

Chen

Arkin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, it would be important to study the ultra‐localization of CDC components at the basal body and how they interact with each other to form structurally normal cilia. It is noteworthy that proteins mutated in ciliopathies are localized to the transition zone (Garcia‐Gonzalo et al , 2011; Huang et al , 2011; Li et al , 2011). …”

Section: Discussionmentioning

confidence: 99%

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

et al. 2016

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A mutation in the centrosomal‐P4.1‐associated protein (CPAP) causes Seckel syndrome with microcephaly, which is suggested to arise from a decline in neural progenitor cells (NPCs) during development. However, mechanisms of NPCs maintenance remain unclear. Here, we report an unexpected role for the cilium in NPCs maintenance and identify CPAP as a negative regulator of ciliary length independent of its role in centrosome biogenesis. At the onset of cilium disassembly, CPAP provides a scaffold for the cilium disassembly complex (CDC), which includes Nde1, Aurora A, and OFD1, recruited to the ciliary base for timely cilium disassembly. In contrast, mutated CPAP fails to localize at the ciliary base associated with inefficient CDC recruitment, long cilia, retarded cilium disassembly, and delayed cell cycle re‐entry leading to premature differentiation of patient iPS‐derived NPCs. Aberrant CDC function also promotes premature differentiation of NPCs in Seckel iPS‐derived organoids. Thus, our results suggest a role for cilia in microcephaly and its involvement during neurogenesis and brain size control.

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“…B9D1 and CC2D2A colocalize at the transition zone of the cilium and belong to a conglomerate of proteins called the B9 complex. [31][32][33][34] Several other JBS proteins are also predicted to be part of this complex. These simultaneous variants in CC2D2A and B9D1 may suggest a digenic or triallelic inheritance model given the functional interaction between the two proteins.…”

Section: Non-mendelian Inheritance and B9d1mentioning

confidence: 99%

Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

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Joubert syndrome (JBS) is a rare neurodevelopmental disorder belonging to the group of ciliary diseases. JBS is genetically heterogeneous, with 420 causative genes identified to date. A molecular diagnosis of JBS is essential for prediction of disease progression and genetic counseling. We developed a targeted next-generation sequencing (NGS) approach for parallel sequencing of 22 known JBS genes plus 599 additional ciliary genes. This method was used to genotype a cohort of 51 well-phenotyped Northern European JBS cases (in some of the cases, Sanger sequencing of individual JBS genes had been performed previously). Altogether, 21 of the 51 cases (41%) harbored biallelic pathogenic mutations in known JBS genes, including 14 mutations not previously described. Mutations in C5orf42 (12%), TMEM67 (10%), and AHI1 (8%) were the most prevalent. C5orf42 mutations result in a purely neurological Joubert phenotype, in one case associated with postaxial polydactyly. Our study represents a population-based cohort of JBS patients not enriched for consanguinity, providing insight into the relative importance of the different JBS genes in a Northern European population. Mutations in C5orf42 are relatively frequent (possibly due to a Dutch founder mutation) and mutations in CEP290 are underrepresented compared with international cohorts. Furthermore, we report a case with heterozygous mutations in CC2D2A and B9D1, a gene associated with the more severe Meckel-Gruber syndrome that was recently published as a potential new JBS gene, and discuss the significance of this finding.

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A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition

Cited by 576 publications

References 49 publications

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

Joubert syndrome: genotyping a Northern European patient cohort

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