Msx2 gene dosage influences the number of proliferative osteogenic cells in growth centers of the developing murine skull:: A possible mechanism for MSX2-mediated craniosynostosis in humans
Msx2 gene dosage influences the number of proliferative osteogenic cells in growth centers of the developing murine skull:: A possible mechanism for MSX2-mediated craniosynostosis in humans
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DOI：
10.1006/dbio.1998.9114
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发表时间：
1999-01-15
影响因子：
2.7
通讯作者：
Maxson, RE
中科院分区：
文献类型：
--
作者：
Liu, YH;Tang, ZQ;Maxson, RE
在其复杂的形态发生过程中，脊椎动物的头骨必须同时保护大脑并扩张以适应其生长。允许这种双重作用的关键结构适应是颅骨的骨板与缝合线分离，纤维关节作为生长中心，并允许颅骨随着大脑的扩大而扩张。颅缝早闭，一个或多个颅骨过早融合，导致颅骨形状异常，是一种常见的发育异常，破坏了这一过程。我们以前发现，在人类MSX2基因的同源结构域的一个单一的氨基酸取代与常染色体显性遗传疾病颅缝早闭，波士顿型。该突变增强了Msx2对其靶序列的亲和力，表明该突变通过显性阳性机制起作用。与这一预测一致，我们发现，Msx2的广泛表达的CMV启动子的控制下，导致颅骨侵入矢状缝的一般过表达。在这里，我们使用组织特异性过表达Msx2的颅骨缝，以解决颅缝早闭和头骨形态发生的发展机制。我们证明，Msx2启动子的一个片段指导报告基因表达的细胞内的缝合线的子集。在胚胎晚期和新生儿阶段，该启动子在生长骨内侧的未分化间充质细胞中表达。通过PS，促进剂活性在缝线中降低，在成骨前缘的外缘的未分化成骨细胞中表现出点状模式。在该启动子控制下Msx 2的过表达足以增强铅引起的顶骨向矢状缝的生长。在此表型之前，颅骨成骨前缘的成骨细胞的数量和BrdU标记均增加。这些发现表明，人类MSX2介导的颅缝早闭中的一个重要早期事件是缝中成骨细胞分化的短暂阻滞和随之而来的成骨细胞库的增加，（C）1999学术出版社。
Throughout its complex morphogenesis, the vertebrate skull must at once protect the brain and expand to accommodate its growth. A key structural adaptation that allows this dual role is the separation of the bony plates of the skull with sutures, fibrous joints that serve as growth centers and allow the calvarial bones to expand as the brain enlarges. Craniosynostosis, the premature fusion of one or more calvarial bones with consequent abnormalities in skull shape, is a common developmental anomaly that disrupts this process. We found previously that a single amino acid substitution in the homeodomain of the human MSX2 gene is associated with the autosomal dominant disorder craniosynostosis, Boston type. This mutation enhances the affinity of Msx2 for its target sequence, suggesting that the mutation acts by a dominant positive mechanism. Consistent with this prediction, we showed that general overexpression of Msx2 under the control of the broadly expressed CMV promoter causes the calvarial bones to invade the sagittal suture. Here we use tissue-specific overexpression of Msx2 within the calvarial sutures to address the developmental mechanisms of craniosynostosis and skull morphogenesis. We demonstrate that a segment of the Msx2 promoter directs reporter gene expression to subsets of cells within the sutures. In late embryonic and neonatal stages, this promoter is expressed in undifferentiated mesenchymal cells medial to the growing bone. By PS, promoter activity is reduced in the suture, exhibiting a punctate pattern in undifferentiated osteoblastic cells in the outer margin of the osteogenic front. Overexpression of Msx2 under the control of this promoter is sufficient to enhance parietal bone growth into the sagittal suture by Pb. This phenotype is preceded by an increase in both the number and the BrdU labeling of osteoblastic cells in the osteogenic fronts of the calvarial bones. These findings suggest that an important early event in MSX2-mediated craniosynostosis in humans is a transient retardation of osteogenic cell differentiation in the suture and a consequent increase in the pool of osteogenic cells, (C) 1999 Academic Press.