Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization
Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization
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DOI：
10.1073/pnas.111092198
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发表时间：
2001-06-05
影响因子：
11.1
通讯作者：
de Crombrugghe, B
中科院分区：
文献类型：
--
作者：
Bi, WM;Huang, WD;de Crombrugghe, B
在人类中，SOX 9杂合突变导致严重的骨骼畸形综合征，即肢端发育不良。除了临床描述外，对该病的发病机制知之甚少。我们已经产生了杂合子Sox 9突变小鼠，表型复制大多数骨骼异常的这种综合征。Sox 9（+/-）小鼠围产期死亡，伴有腭裂，以及发育不全和软骨前体衍生的许多骨骼结构弯曲。在胚胎天（E）14.5杂合子胚胎，弯曲的半径，尺骨，胫骨软骨已经突出。E12.5杂合子。用阿尔新蓝显示的所有骨骼元素都较小。此外，E10.5和E12.5时Col 2a 1 RNA的总体水平低于野生型胚胎。我们认为，在胚胎后期观察到的骨骼异常是由延迟或有缺陷的前软骨冷凝。此外，在E18.5胚胎和新生杂合子中。在许多骨中发生过早矿化，包括椎骨和一些颅面骨。因为Sox 9在生长板的矿化部分中不表达，所以这种过早矿化很可能是表达Sox 9的生长板细胞中存在的等位基因不足的结果。由于杂合Sox 9突变体的肥大区大于野生型小鼠，我们建议Sox 9也有调节过渡到肥大的软骨细胞在生长板中的作用。尽管软骨严重发育不全，但生长板的整体组织和细胞组成是正常的。我们的研究结果表明，软骨细胞分化途径的两个关键步骤是敏感的Sox 9剂量的假设，第一，早期的步骤，大概在软骨原基的间充质凝聚的阶段，第二，后期的步骤之前的软骨细胞过渡到肥大的软骨细胞。
In humans, SOX9 heterozygous mutations cause the severe skeletal dysmorphology syndrome campomelic dysplasia. Except for clinical descriptions, little is known about the pathogenesis of this disease. We have generated heterozygous Sox9 mutant mice that phenocopy most of the skeletal abnormalities of this syndrome. The Sox9(+/-) mice died perinatally with cleft palate, as well as hypoplasia and bending of many skeletal structures derived from cartilage precursors. In embryonic day (E)14.5 heterozygous embryos, bending of radius, ulna, and tibia cartilages was already prominent. In E12.5 heterozygotes. all skeletal elements visualized by using Alcian blue were smaller. In addition, the overall levels of Col2a1 RNA at E10.5 and E12.5 were lower than in wild-type embryos. We propose that the skeletal abnormalities observed at later embryonic stages were caused by delayed or defective precartilaginous condensations. Furthermore, in E18.5 embryos and in newborn heterozygotes. premature mineralization occurred in many bones, including vertebrae and some craniofacial bones. Because Sox9 is not expressed in the mineralized portion of the growth plate, this premature mineralization is very likely the consequence of allele insufficiency existing in cells of the growth plate that express Sox9. Because the hypertrophic zone of the heterozygous Sox9 mutants was larger than that of wild-type mice, we propose that Sox9 also has a role in regulating the transition to hypertrophic chondrocytes in the growth plate. Despite the severe hypoplasia of cartilages, the overall organization and cellular composition of the growth plate were otherwise normal. Our results suggest the hypothesis that two critical steps of the chondrocyte differentiation pathway are sensitive to Sox9 dosage, First, an early step presumably at the stage of mesenchymal condensation of cartilage primordia, and second, a later step preceding the transition of chondrocytes into hypertrophic chondrocytes.