Abstract：
Ciliopathies are genetic syndromes that link skeletal dysplasias to the dysfunction of primary cilia. Primary cilia are sensory organelles synthesized by intraflagellar transport (IFT)-A and B complexes, which traffic protein cargo along a microtubular core. We have reported that the deletion of the IFT-A gene, Thm2, together with a null allele of its paralog, Thm1, causes a small skeleton with a small mandible or micrognathia in juvenile mice. Using micro-computed tomography, here we quantify the craniofacial defects of Thm2-/-; Thm1aln/+ triple allele mutant mice. At postnatal day 14, triple allele mutant mice exhibited micrognathia, midface hypoplasia, and a decreased facial angle due to shortened upper jaw length, premaxilla, and nasal bones, reflecting altered development of facial anterior-posterior elements. Mutant mice also showed increased palatal width, while other aspects of the facial transverse, as well as vertical dimensions, remained intact. As such, other ciliopathy-related craniofacial defects, such as cleft lip and/or palate, hypo-/hypertelorism, broad nasal bridge, craniosynostosis, and facial asymmetry, were not observed. Calvarial-derived osteoblasts of triple allele mutant mice showed reduced bone formation in vitro that was ameliorated by Hedgehog agonist, SAG. Together, these data indicate that Thm2 and Thm1 genetically interact to regulate bone formation and sculpting of the postnatal face. The triple allele mutant mice present a novel model to study craniofacial bone development.
摘要：
纤毛病是将骨骼发育不良与原发性纤毛功能障碍联系起来的遗传综合征。初级纤毛是由滑膜内运输（IFT）-A和B复合物合成的感觉器官，沿着微管核心运送蛋白质货物。我们已经报道了IFT-A基因的缺失，Thm2，以及它的同系物的无效等位基因，Thm1在幼年小鼠中引起具有小下颌骨或小下颌骨的小骨骼。用微型计算机断层扫描,在这里，我们量化了Thm2-/-;Thm1aln/+三等位基因突变小鼠的颅面缺陷。在出生后第14天，三等位基因突变小鼠表现出小颌畸形，脸中部发育不全,由于上颌长度缩短，面部角度减小，前颌骨,和鼻骨，反映面部前后元素发育的改变。突变小鼠还显示出增加的腭宽度，而面部横向的其他方面，以及垂直尺寸，保持完好无损。因此，其他纤毛病相关颅面缺损，如唇裂和/或腭裂，低/超端化，宽阔的鼻梁，颅骨融合症,和面部不对称，没有被观察到。三等位基因突变小鼠的颅骨来源的成骨细胞在体外显示出减少的骨形成，这被Hedgehog激动剂改善。SAG.一起,这些数据表明Thm2和Thm1基因相互作用以调节出生后面部的骨形成和雕刻。三等位基因突变小鼠为研究颅面骨发育提供了一种新的模型。
