Msx2 and Twist cooperatively control the development of the neural crest-derived skeletogenic mesenchyme of the murine skull vault
Msx2 and Twist cooperatively control the development of the neural crest-derived skeletogenic mesenchyme of the murine skull vault
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DOI：
10.1242/dev.00793
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发表时间：
2003-12-01
期刊：
影响因子：
4.6
通讯作者：
Maxson, RE
中科院分区：
文献类型：
--
作者：
Ishii, M;Merrill, AE;Maxson, RE
脊椎动物头骨拱顶的平骨由两个迁移的间充质细胞群，颅神经嵴和近轴中胚层发育而来。在颅骨穹窿发育开始时，这些间充质细胞从它们的起源位置迁移到外胚层和发育中的大脑半球之间的位置。它们在那里结合、增殖并沿着成骨途径分化。颅骨拱顶发育异常在人类中相对常见。其中一种异常是家族性颅孔，即颅骨顶内持续未僵化的区域。已知MSX2和TWIST的突变会导致人类的颅孔。这种缺陷背后的细胞和发育过程所知甚少。也不知道MSX2和TWIST是否在相同或不同的途径中起作用。我们将Msx2突变小鼠颅骨孔缺损的起源追溯到构成额骨基础的一组成骨间充质细胞。我们发现这种细胞群的减少不是因为神经嵴源性前体细胞的凋亡或迁移不足，而是因为其分化和增殖的缺陷。此外，我们还证明，扭曲功能的杂合缺失导致颅骨穹窿的孔与Msx2功能缺失导致的孔相似。与单个突变体相比，Msx2-Twist双突变体的额骨成骨间充质数量和增殖均减少。因此，Msx2和Twist共同调控成骨间质的分化和增殖。分子上位性分析表明，Msx2和Twist并不是串联作用来控制成骨细胞分化，而是在相同的上位性水平上起作用。
The flat bones of the vertebrate skull vault develop from two migratory mesenchymal cell populations, the cranial neural crest and paraxial mesoderm. At the onset of skull vault development, these mesenchymal cells emigrate from their sites of origin to positions between the ectoderm and the developing cerebral hemispheres. There they combine, proliferate and differentiate along an osteogenic pathway. Anomalies in skull vault development are relatively common in humans. One such anomaly is familial calvarial foramina, persistent unossified areas within the skull vault. Mutations in MSX2 and TWIST are known to cause calvarial foramina in humans. Little is known of the cellular and developmental processes underlying this defect. Neither is it known whether MSX2 and TWIST function in the same or distinct pathways. We trace the origin of the calvarial foramen defect in Msx2 mutant mice to a group of skeletogenic mesenchyme cells that compose the frontal bone rudiment. We show that this cell population is reduced not because of apoptosis or deficient migration of neural crest-derived precursor cells, but because of defects in its differentiation and proliferation. We demonstrate, in addition, that heterozygous loss of Twist function causes a foramen in the skull vault similar to that caused by loss of Msx2 function. Both the quantity and proliferation of the frontal bone skeletogenic mesenchyme are reduced in Msx2-Twist double mutants compared with individual mutants. Thus Msx2 and Twist cooperate in the control of the differentiation and proliferation of skeletogenic mesenchyme. Molecular epistasis analysis suggests that Msx2 and Twist do not act in tandem to control osteoblast differentiation, but function at the same epistatic level.