Twist1 dimer selection regulates cranial suture patterning and fusion
Twist1 dimer selection regulates cranial suture patterning and fusion
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DOI：
10.1002/dvdy.20717
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发表时间：
2006-05-01
影响因子：
2.5
通讯作者：
Spicer, Douglas B.
中科院分区：
文献类型：
--
作者：
Connerney, Jeannette;Andreeva, Viktoria;Spicer, Douglas B.
Saethre-Chotzen综合征与碱性螺旋环螺旋（bHLH）转录因子TWIST 1的单倍不足有关，其特征是颅缝过早闭合，称为颅缝早闭;然而，这种缺陷的机制尚不清楚。Twist 1已被证明在间充质特化和分化中发挥积极和消极的作用，在这里，我们表明Twist 1的活性依赖于其二聚体伴侣。Twist 1与E2 A E蛋白形成同源二聚体（T/T）和异源二聚体（T/E），Twist 1与HLH抑制剂Id蛋白的相对水平决定形成哪种二聚体。根据Twist 1和Id 1在颅缝中的表达模式，我们假设Twist 1在成骨前缘形成同源二聚体，在中间缝形成T/E异源二聚体。为了支持这一假设，我们发现由T/T同源二聚体调控的基因，如FGFR 2和骨膜蛋白，在成骨前表达，而由T/E异源二聚体调控的基因，如血小板反应蛋白-1，在中间缝合处表达。这些二聚体之间的比例在Ttvist 1 +/-小鼠的缝线中改变，有利于同型二聚体的增加和成骨前沿的扩张。值得注意的是，冠状缝的T/T与T/E比值大于矢状缝，这一发现可能有助于使冠状缝更容易因TWIST单倍功能不全而融合。重要的是，我们能够通过调节这些二聚体之间的平衡，通过增加E2 A E12的表达或通过降低Id的表达，抑制Twist 1 +/-小鼠的缝线融合。因此，我们已经确定二聚体伴侣选择作为Twist 1功能的重要介质，并提供了一个机制的理解，由于TWIST单倍不足的颅缝早闭。发展动力学235：1345-1357，2006年。(c)2006威利-利斯公司
Saethre-Chotzen syndrome is associated with haploinsufficiency of the basic-helix-loop-helix (bHLH) transcription factor TWIST1 and is characterized by premature closure of the cranial sutures, termed craniosynostosis; however, the mechanisms underlying this defect are unclear. Twist1 has been shown to play both positive and negative roles in mesenchymal specification and differentiation, and here we show that the activity of Twist1 is dependent on its dimer partner. Twist1 forms both homodimers (T/T) and heterodimers with E2A E proteins (T/E) and the relative level of Twist1 to the HLH inhibitor Id proteins determines which dimer forms. On the basis of the expression patterns of Twist1 and Id1 within the cranial sutures, we hypothesized that Twist1 forms homodimers in the osteogenic fronts and T/E heterodimers in the mid-sutures. In support of this hypothesis, we have found that genes regulated by T/T homodimers, such as FGFR2 and periostin, are expressed in the osteogenic fronts, whereas genes regulated by T/E heterodimers, such as thrombospondin-1, are expressed in the mid-sutures. The ratio between these dimers is altered in the sutures of Ttvist1+/- mice, favoring an increase in homodimers and an expansion of the osteogenic fronts. Of interest, the T/T to T/E ratio is greater in the coronal versus the sagittal suture, and this finding may contribute to making the coronal suture more susceptible to fusion due to TWIST haploinsufficiency. Importantly, we were able to inhibit suture fusion in Twist1 +/- mice by modulating the balance between these dimers toward T/E formation, by either increasing the expression of E2A E12 or by decreasing Id expression. Therefore, we have identified dimer partner selection as an important mediator of Twist1 function and provide a mechanistic understanding of craniosynostosis due to TWIST haploinsufficiency. Developmental Dynamics 235:1345-1357, 2006. (c) 2006 Wiley-Liss, Inc.