Limits...
The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.

Thauvin-Robinet C, Lee JS, Lopez E, Herranz-Pérez V, Shida T, Franco B, Jego L, Ye F, Pasquier L, Loget P, Gigot N, Aral B, Lopes CA, St-Onge J, Bruel AL, Thevenon J, González-Granero S, Alby C, Munnich A, Vekemans M, Huet F, Fry AM, Saunier S, Rivière JB, Attié-Bitach T, Garcia-Verdugo JM, Faivre L, Mégarbané A, Nachury MV - Nat. Genet. (2014)

Bottom Line: How centriole length is precisely set remains elusive.Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene.Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.

View Article: PubMed Central - PubMed

Affiliation: 1] Equipe d'Accueil 4271 Génétique des Anomalies du Développement, Fédération Hospitalo-Universitaire, Université de Bourgogne, Dijon, France. [2] Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs" de l'Est, Centre de Génétique et Pédiatrie 1, Hôpital d'Enfants, Centre Hospitalier Universitaire Dijon, Dijon, France. [3].

ABSTRACT
Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.

Show MeSH

Related in: MedlinePlus

C2cd3 promotes assembly of microtubule structures with centriolar features(a) CLEM of cytoplasmic GFP-C2cd3 filaments. N, nucleus; m, mitochondria. Scale bar 5 µm (fluorescence panels), 500 nm (EM panels).(b) U2OS osteosarcoma cells transfected with GFP-C2cd3 were stained for centrin (red), acetylated tubulin (magenta) and DNA (blue). Scale bar 5 µm.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4120243&req=5

Figure 6: C2cd3 promotes assembly of microtubule structures with centriolar features(a) CLEM of cytoplasmic GFP-C2cd3 filaments. N, nucleus; m, mitochondria. Scale bar 5 µm (fluorescence panels), 500 nm (EM panels).(b) U2OS osteosarcoma cells transfected with GFP-C2cd3 were stained for centrin (red), acetylated tubulin (magenta) and DNA (blue). Scale bar 5 µm.

Mentions: In addition to hyperelongated centrioles, overexpressed GFP-C2cd3 was found alongside bright microtubules rods (Supplementary Fig. 7c) enriched in acetylated tubulin in various regions of the cytoplasm (Fig. 5a). Similar to prior observations with CPAP overexpression3, CLEM revealed that these cytoplasmic microtubules structures are reminiscent of centrioles, albeit much less organized. The mixed C2cd3/microtubule rods contained microtubules spaced 250nm apart by an electron dense matrix (Fig. 6a) and doublet microtubules could sometime be distinguished (Fig. 6a, lower panel). Congruently, the C2cd3/microtubule rods were positive for centrin (Fig. 6b). While the biogenesis of these centriole-like structures is presently unknown, they may have originated and then broken off from hyperelongated centrioles (see Supplementary Fig. 7b and Supplementary Video 1).


The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.

Thauvin-Robinet C, Lee JS, Lopez E, Herranz-Pérez V, Shida T, Franco B, Jego L, Ye F, Pasquier L, Loget P, Gigot N, Aral B, Lopes CA, St-Onge J, Bruel AL, Thevenon J, González-Granero S, Alby C, Munnich A, Vekemans M, Huet F, Fry AM, Saunier S, Rivière JB, Attié-Bitach T, Garcia-Verdugo JM, Faivre L, Mégarbané A, Nachury MV - Nat. Genet. (2014)

C2cd3 promotes assembly of microtubule structures with centriolar features(a) CLEM of cytoplasmic GFP-C2cd3 filaments. N, nucleus; m, mitochondria. Scale bar 5 µm (fluorescence panels), 500 nm (EM panels).(b) U2OS osteosarcoma cells transfected with GFP-C2cd3 were stained for centrin (red), acetylated tubulin (magenta) and DNA (blue). Scale bar 5 µm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4120243&req=5

Figure 6: C2cd3 promotes assembly of microtubule structures with centriolar features(a) CLEM of cytoplasmic GFP-C2cd3 filaments. N, nucleus; m, mitochondria. Scale bar 5 µm (fluorescence panels), 500 nm (EM panels).(b) U2OS osteosarcoma cells transfected with GFP-C2cd3 were stained for centrin (red), acetylated tubulin (magenta) and DNA (blue). Scale bar 5 µm.
Mentions: In addition to hyperelongated centrioles, overexpressed GFP-C2cd3 was found alongside bright microtubules rods (Supplementary Fig. 7c) enriched in acetylated tubulin in various regions of the cytoplasm (Fig. 5a). Similar to prior observations with CPAP overexpression3, CLEM revealed that these cytoplasmic microtubules structures are reminiscent of centrioles, albeit much less organized. The mixed C2cd3/microtubule rods contained microtubules spaced 250nm apart by an electron dense matrix (Fig. 6a) and doublet microtubules could sometime be distinguished (Fig. 6a, lower panel). Congruently, the C2cd3/microtubule rods were positive for centrin (Fig. 6b). While the biogenesis of these centriole-like structures is presently unknown, they may have originated and then broken off from hyperelongated centrioles (see Supplementary Fig. 7b and Supplementary Video 1).

Bottom Line: How centriole length is precisely set remains elusive.Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene.Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.

View Article: PubMed Central - PubMed

Affiliation: 1] Equipe d'Accueil 4271 Génétique des Anomalies du Développement, Fédération Hospitalo-Universitaire, Université de Bourgogne, Dijon, France. [2] Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs" de l'Est, Centre de Génétique et Pédiatrie 1, Hôpital d'Enfants, Centre Hospitalier Universitaire Dijon, Dijon, France. [3].

ABSTRACT
Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.

Show MeSH
Related in: MedlinePlus