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Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling.

Yee LE, Garcia-Gonzalo FR, Bowie RV, Li C, Kennedy JK, Ashrafi K, Blacque OE, Leroux MR, Reiter JF - PLoS Genet. (2015)

Bottom Line: Similarly, disruption of an NPHP complex component and the BBS complex component BBS-5 individually did not compromise ciliary structure, but together did.However, disrupting both Tctn1 and either Nphp1 or Nphp4 exacerbated defects in ciliogenesis and cilia-associated developmental signaling, as did disrupting both Tctn1 and the BBSome component Bbs1.Thus, we demonstrate that ciliary complexes act in parallel to support ciliary function and suggest that human ciliopathy phenotypes are altered by genetic interactions between different ciliary biochemical complexes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.

ABSTRACT
Mutations in genes encoding cilia proteins cause human ciliopathies, diverse disorders affecting many tissues. Individual genes can be linked to ciliopathies with dramatically different phenotypes, suggesting that genetic modifiers may participate in their pathogenesis. The ciliary transition zone contains two protein complexes affected in the ciliopathies Meckel syndrome (MKS) and nephronophthisis (NPHP). The BBSome is a third protein complex, affected in the ciliopathy Bardet-Biedl syndrome (BBS). We tested whether mutations in MKS, NPHP and BBS complex genes modify the phenotypic consequences of one another in both C. elegans and mice. To this end, we identified TCTN-1, the C. elegans ortholog of vertebrate MKS complex components called Tectonics, as an evolutionarily conserved transition zone protein. Neither disruption of TCTN-1 alone or together with MKS complex components abrogated ciliary structure in C. elegans. In contrast, disruption of TCTN-1 together with either of two NPHP complex components, NPHP-1 or NPHP-4, compromised ciliary structure. Similarly, disruption of an NPHP complex component and the BBS complex component BBS-5 individually did not compromise ciliary structure, but together did. As in nematodes, disrupting two components of the mouse MKS complex did not cause additive phenotypes compared to single mutants. However, disrupting both Tctn1 and either Nphp1 or Nphp4 exacerbated defects in ciliogenesis and cilia-associated developmental signaling, as did disrupting both Tctn1 and the BBSome component Bbs1. Thus, we demonstrate that ciliary complexes act in parallel to support ciliary function and suggest that human ciliopathy phenotypes are altered by genetic interactions between different ciliary biochemical complexes.

No MeSH data available.


Related in: MedlinePlus

Mouse Tctn1 genetically interacts with NPHP complex genes, but not MKS complex genes.(A) Lateral views of wild type, single or double mutant mouse embryos of indicated genotype at E14.5. Exencephaly is apparent in the Tctn1-/-Nphp1-/- double mutant. Corresponding Alcian blue staining of the right forelimb (top) and hindlimb (bottom) are included, with asterisks indicating extra digits. Genes encoding components of the NPHP complex are indicated in red. Genes encoding components of the MKS complex are indicated in green. Scale bars, 1 mm. (B) Number of digits in the forelimbs and (C) hindlimbs of wild type, single or double mutant embryos of indicated genotypes. (D) Incidence of exencephaly in wild type, single or double mutants embryos of indicated genotypes. Numbers of animals analyzed for polydactyly and exencephaly are included in S1 and S2 Tables.
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pgen.1005627.g005: Mouse Tctn1 genetically interacts with NPHP complex genes, but not MKS complex genes.(A) Lateral views of wild type, single or double mutant mouse embryos of indicated genotype at E14.5. Exencephaly is apparent in the Tctn1-/-Nphp1-/- double mutant. Corresponding Alcian blue staining of the right forelimb (top) and hindlimb (bottom) are included, with asterisks indicating extra digits. Genes encoding components of the NPHP complex are indicated in red. Genes encoding components of the MKS complex are indicated in green. Scale bars, 1 mm. (B) Number of digits in the forelimbs and (C) hindlimbs of wild type, single or double mutant embryos of indicated genotypes. (D) Incidence of exencephaly in wild type, single or double mutants embryos of indicated genotypes. Numbers of animals analyzed for polydactyly and exencephaly are included in S1 and S2 Tables.

Mentions: To assess potential genetic interactions between the MKS and NPHP complexes in mammals, we generated mice doubly mutant for Tctn1 and Nphp4. Tctn1-/- mutants exhibited single digit polydactyly restricted to the hindlimbs and Nphp4n/n mutants had no limb abnormalities. In contrast, Tctn1-/-Nphp4n/n double mutants exhibited polydactyly in both the forelimb and hindlimb, and had an increased number of digits per limb compared to the polydactyly of Tctn1-/- mutants (Fig 5A–5C, S1 Table). In addition, Tctn1-/-Nphp4n/n double mutants exhibited partially penetrant exencephaly, which was not observed in Tctn1-/- single mutants or in Nphp4n/n single mutants (Fig 5D, S2 Table). Therefore, Tctn1 and Nphp4 interact synergistically in mammals, as they do in C. elegans.


Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling.

Yee LE, Garcia-Gonzalo FR, Bowie RV, Li C, Kennedy JK, Ashrafi K, Blacque OE, Leroux MR, Reiter JF - PLoS Genet. (2015)

Mouse Tctn1 genetically interacts with NPHP complex genes, but not MKS complex genes.(A) Lateral views of wild type, single or double mutant mouse embryos of indicated genotype at E14.5. Exencephaly is apparent in the Tctn1-/-Nphp1-/- double mutant. Corresponding Alcian blue staining of the right forelimb (top) and hindlimb (bottom) are included, with asterisks indicating extra digits. Genes encoding components of the NPHP complex are indicated in red. Genes encoding components of the MKS complex are indicated in green. Scale bars, 1 mm. (B) Number of digits in the forelimbs and (C) hindlimbs of wild type, single or double mutant embryos of indicated genotypes. (D) Incidence of exencephaly in wild type, single or double mutants embryos of indicated genotypes. Numbers of animals analyzed for polydactyly and exencephaly are included in S1 and S2 Tables.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4635004&req=5

pgen.1005627.g005: Mouse Tctn1 genetically interacts with NPHP complex genes, but not MKS complex genes.(A) Lateral views of wild type, single or double mutant mouse embryos of indicated genotype at E14.5. Exencephaly is apparent in the Tctn1-/-Nphp1-/- double mutant. Corresponding Alcian blue staining of the right forelimb (top) and hindlimb (bottom) are included, with asterisks indicating extra digits. Genes encoding components of the NPHP complex are indicated in red. Genes encoding components of the MKS complex are indicated in green. Scale bars, 1 mm. (B) Number of digits in the forelimbs and (C) hindlimbs of wild type, single or double mutant embryos of indicated genotypes. (D) Incidence of exencephaly in wild type, single or double mutants embryos of indicated genotypes. Numbers of animals analyzed for polydactyly and exencephaly are included in S1 and S2 Tables.
Mentions: To assess potential genetic interactions between the MKS and NPHP complexes in mammals, we generated mice doubly mutant for Tctn1 and Nphp4. Tctn1-/- mutants exhibited single digit polydactyly restricted to the hindlimbs and Nphp4n/n mutants had no limb abnormalities. In contrast, Tctn1-/-Nphp4n/n double mutants exhibited polydactyly in both the forelimb and hindlimb, and had an increased number of digits per limb compared to the polydactyly of Tctn1-/- mutants (Fig 5A–5C, S1 Table). In addition, Tctn1-/-Nphp4n/n double mutants exhibited partially penetrant exencephaly, which was not observed in Tctn1-/- single mutants or in Nphp4n/n single mutants (Fig 5D, S2 Table). Therefore, Tctn1 and Nphp4 interact synergistically in mammals, as they do in C. elegans.

Bottom Line: Similarly, disruption of an NPHP complex component and the BBS complex component BBS-5 individually did not compromise ciliary structure, but together did.However, disrupting both Tctn1 and either Nphp1 or Nphp4 exacerbated defects in ciliogenesis and cilia-associated developmental signaling, as did disrupting both Tctn1 and the BBSome component Bbs1.Thus, we demonstrate that ciliary complexes act in parallel to support ciliary function and suggest that human ciliopathy phenotypes are altered by genetic interactions between different ciliary biochemical complexes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.

ABSTRACT
Mutations in genes encoding cilia proteins cause human ciliopathies, diverse disorders affecting many tissues. Individual genes can be linked to ciliopathies with dramatically different phenotypes, suggesting that genetic modifiers may participate in their pathogenesis. The ciliary transition zone contains two protein complexes affected in the ciliopathies Meckel syndrome (MKS) and nephronophthisis (NPHP). The BBSome is a third protein complex, affected in the ciliopathy Bardet-Biedl syndrome (BBS). We tested whether mutations in MKS, NPHP and BBS complex genes modify the phenotypic consequences of one another in both C. elegans and mice. To this end, we identified TCTN-1, the C. elegans ortholog of vertebrate MKS complex components called Tectonics, as an evolutionarily conserved transition zone protein. Neither disruption of TCTN-1 alone or together with MKS complex components abrogated ciliary structure in C. elegans. In contrast, disruption of TCTN-1 together with either of two NPHP complex components, NPHP-1 or NPHP-4, compromised ciliary structure. Similarly, disruption of an NPHP complex component and the BBS complex component BBS-5 individually did not compromise ciliary structure, but together did. As in nematodes, disrupting two components of the mouse MKS complex did not cause additive phenotypes compared to single mutants. However, disrupting both Tctn1 and either Nphp1 or Nphp4 exacerbated defects in ciliogenesis and cilia-associated developmental signaling, as did disrupting both Tctn1 and the BBSome component Bbs1. Thus, we demonstrate that ciliary complexes act in parallel to support ciliary function and suggest that human ciliopathy phenotypes are altered by genetic interactions between different ciliary biochemical complexes.

No MeSH data available.


Related in: MedlinePlus