Cleft palate defect of Dlx1/2-/- mutant mice is caused by lack of vertical outgrowth in the posterior palate.
Cleft palate defect of Dlx1/2-/- mutant mice is caused by lack of vertical outgrowth in the posterior palate.
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DOI：
10.1002/dvdy.23867
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发表时间：
2012-11
影响因子：
2.5
通讯作者：
Rubenstein, John L. R.
中科院分区：
文献类型：
--
作者：
Jeong, Juhee;Cesario, Jeffry;Zhao, Yangu;Burns, Lorel;Westphal, Heiner;Rubenstein, John L. R.
缺乏Dlx1和Dlx2(Dlx1/2−/−)活性的小鼠会出现腭裂，这是人类最常见的先天性缺陷之一，但这种表型背后的病因尚不清楚。因此，我们分析了Dlx1和Dlx2失活引起的形态、细胞和分子变化与腭部发育有关。Dlx1/2−/−突变体在腭裂发生的早期，后腭部缺乏垂直生长。我们将这种生长缺陷归因于细胞增殖减少。细胞周期调节因子Ccnd1的表达在同一区域被特异性下调。以往的研究证实，Shh、Bmp4和Fgf10参与的上皮-间充质信号环在腭部发育过程中对细胞增殖和组织生长具有重要作用。这一信号环在D1x1/2−/−腭部被破坏。然而，有趣的是，D1x1/2−/−突变体中Ccnd1表达的降低和有丝分裂的减少与这个信号循环无关。最后，Dlx1/2活性是几个转录因子基因正常表达所必需的，这些基因的突变会导致腭裂。Dlx1和Dlx2的功能对后腭架的初始形成至关重要，Dlx基因位于多种信号分子和转录因子的上游，这些分子和转录因子对腭裂形成的后期阶段至关重要。
Mice lacking the activities of Dlx1 and Dlx2 (Dlx1/2−/−) exhibit cleft palate, one of the most common human congenital defects, but the etiology behind this phenotype has been unknown. Therefore, we analyzed the morphological, cellular, and molecular changes caused by inactivation of Dlx1 and Dlx2 as related to palate development. Dlx1/2−/− mutants exhibited lack of vertical growth in the posterior palate during the earliest stage of palatogenesis. We attributed this growth deficiency to reduced cell proliferation. Expression of a cell cycle regulator Ccnd1 was specifically down-regulated in the same region. Previous studies established that the epithelial-mesenchymal signaling loop involving Shh, Bmp4 and Fgf10 is important for cell proliferation and tissue growth during palate development. This signaling loop was disrupted in Dlx1/2−/− palate. Interestingly, however, the decreases in Ccnd1 expression and mitosis in Dlx1/2−/− mutants were independent of this signaling loop. Finally, Dlx1/2 activity was required for normal expression of several transcription factor genes whose mutation results in palate defects. The functions of Dlx1 and Dlx2 are crucial for the initial formation of the posterior palatal shelves, and that the Dlx genes lie upstream of multiple signaling molecules and transcription factors important for later stages of palatogenesis.
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DOI：
10.1242/dev.019778
发表时间：
2008-09
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Jeong J;Li X;McEvilly RJ;Rosenfeld MG;Lufkin T;Rubenstein JL
通讯作者：
Rubenstein JL
影响因子：
16.2
作者：
Choi, GB;Dong, HW;Anderson, DJ
通讯作者：
Anderson, DJ
影响因子：
2.7
作者：
Denaxa, Myrto;Sharpe, Paul T.;Pachnis, Vassilis
通讯作者：
Pachnis, Vassilis
影响因子：
4.6
作者：
Ito, Y;Yeo, JY;Chai, Y
通讯作者：
Chai, Y
影响因子：
2.6
作者：
BULFONE, A;KIM, HJ;RUBENSTEIN, JLR
通讯作者：
RUBENSTEIN, JLR