The cellular and molecular etiology of the craniofacial defects in the avian ciliopathic mutant talpid2.
The cellular and molecular etiology of the craniofacial defects in the avian ciliopathic mutant talpid2.
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DOI：
10.1242/dev.105924
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发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Brugmann SA
中科院分区：
文献类型：
--
作者：
Chang CF;Schock EN;O'Hare EA;Dodgson J;Cheng HH;Muir WM;Edelmann RE;Delany ME;Brugmann SA
talpid 2是一种禽类常染色体隐性突变体，具有多种先天性畸形，包括多指畸形和面裂。虽然talpid 3的表型相似，talpid 2具有独特的面部表型和未知的细胞，分子和遗传基础。我们着手确定这种突变的颅面表型的病因。我们证实，初级纤毛在talpid2突变体中被破坏。在分子上，我们发现Hedgehog信号的中断。GLI2和GLI3的翻译后加工在发育中的面部发育中是异常的。虽然在talpid2突变体中GLI2和GLI3加工都被破坏，但在细胞核中只有GLI3激活剂水平发生了显著改变。通过额外的精细定位和全基因组测序，我们确定talpid2表型与GGA1q上的1.4 Mb区域相关，该区域包含编码纤毛蛋白C2CD3的基因。 我们克隆了C2CD3的鸟类直系同源物，发现它的表达是普遍存在的，但在发育中的四肢和面部神经中最强大。此外，我们发现C2CD3定位于近端的纤毛轴丝，是重要的对接的纤毛囊泡和细胞膜的母亲中心粒。最后，我们确定了一个19 bp的缺失talpid2 C2CD3产生一个提前终止密码子，因此截短的蛋白质，作为可能的致病等位基因的表型。 总之，这些数据提供了对talpid 2表型的细胞、分子和遗传病因学的深入了解。我们的数据表明，虽然talpid2和talpid3突变影响一个共同的纤毛发生途径，它们是由不同的纤毛蛋白的突变，导致颅面表型的差异。
talpid2 is an avian autosomal recessive mutant with a myriad of congenital malformations, including polydactyly and facial clefting. Although phenotypically similar to talpid3, talpid2 has a distinct facial phenotype and an unknown cellular, molecular and genetic basis. We set out to determine the etiology of the craniofacial phenotype of this mutant. We confirmed that primary cilia were disrupted in talpid2 mutants. Molecularly, we found disruptions in Hedgehog signaling. Post-translational processing of GLI2 and GLI3 was aberrant in the developing facial prominences. Although both GLI2 and GLI3 processing were disrupted in talpid2 mutants, only GLI3 activator levels were significantly altered in the nucleus. Through additional fine mapping and whole-genome sequencing, we determined that the talpid2 phenotype was linked to a 1.4 Mb region on GGA1q that contained the gene encoding the ciliary protein C2CD3. We cloned the avian ortholog of C2CD3 and found its expression was ubiquitous, but most robust in the developing limbs and facial prominences. Furthermore, we found that C2CD3 is localized proximal to the ciliary axoneme and is important for docking the mother centriole to the ciliary vesicle and cell membrane. Finally, we identified a 19 bp deletion in talpid2 C2CD3 that produces a premature stop codon, and thus a truncated protein, as the likely causal allele for the phenotype. Together, these data provide insight into the cellular, molecular and genetic etiology of the talpid2 phenotype. Our data suggest that, although the talpid2 and talpid3 mutations affect a common ciliogenesis pathway, they are caused by mutations in different ciliary proteins that result in differences in craniofacial phenotype.
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影响因子：
2.9
作者：
Buxton, P;Davey, MG;Tickle, C
通讯作者：
Tickle, C
影响因子：
2.7
作者：
Caruccio, NC;Martinez-Lopez, A;Fallon, JF
通讯作者：
Fallon, JF
影响因子：
30.8
作者：
HUI, CC;JOYNER, AL
通讯作者：
JOYNER, AL
DOI：
10.1242/dev.029835
发表时间：
2008-12
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Hoover AN;Wynkoop A;Zeng H;Jia J;Niswander LA;Liu A
通讯作者：
Liu A
影响因子：
2.5
作者：
Bell, GW;Yatskievych, TA;Antin, PB
通讯作者：
Antin, PB