Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice.
Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice.
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DOI：
10.1002/jbmr.1857
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发表时间：
2013-06
影响因子：
6.2
通讯作者：
Mishina, Yuji
中科院分区：
文献类型：
--
作者：
Komatsu, Yoshihiro;Yu, Paul B.;Kamiya, Nobuhiro;Pan, Haichun;Fukuda, Tomokazu;Scott, Gregory J.;Ray, Manas K.;Yamamura, Ken-ichi;Mishina, Yuji
颅缝早闭描述了婴儿头骨的一个或多个缝过早融合的情况，导致面部畸形和大脑发育延迟。大约20%的人类颅缝早闭被认为是由于基因突变改变生长因子信号传导;然而，这些突变导致颅缝早闭的分子机制还不完全，不同类型的综合征颅缝早闭的致病基因尚未确定。在这里，我们表明，增强骨形态发生蛋白（BMP）信号通过骨形态发生蛋白IA型受体（BMPR 1A）在颅神经嵴细胞，而不是在成骨细胞，导致过早缝融合小鼠。为了支持精确调节BMP信号传导的需要，在Bmpr 1a单倍不足的背景下挽救了该缺陷，并相应地使Smad磷酸化正常化。此外，在体内治疗LDN-193189，BMP I型受体激酶的选择性化学抑制剂导致部分拯救颅缝早闭。在突变小鼠和获救小鼠中均观察到与颅缝早闭有关的成纤维细胞生长因子（FGF）途径的信号增强，这表明FGF信号增强不是该模型中发现的过早融合的唯一原因。Smad依赖性BMP信号的相对适度增强导致过早的颅缝融合，这一发现表明BMP信号失调对综合征性颅缝早闭的重要贡献，以及早期干预的潜在策略。
Craniosynostosis describes conditions in which one or more sutures of the infant skull are prematurely fused, resulting in facial deformity and delayed brain development. Approximately 20% of human craniosynostoses are thought to result from gene mutations altering growth factor signaling; however, the molecular mechanisms by which these mutations cause craniosynostosis are incompletely characterized, and the causative genes for diverse types of syndromic craniosynostosis have yet to be identified. Here, we show that enhanced bone morphogenetic protein (BMP) signaling through the BMP type IA receptor (BMPR1A) in cranial neural crest cells, but not in osteoblasts, causes premature suture fusion in mice. In support of a requirement for precisely regulated BMP signaling, this defect was rescued on a Bmpr1a haploinsufficient background, with corresponding normalization of Smad phosphorylation. Moreover, in vivo treatment with LDN-193189, a selective chemical inhibitor of BMP type I receptor kinases resulted in partial rescue of craniosynostosis. Enhanced signaling of the fibroblast growth factor (FGF) pathway, which has been implicated in craniosynostosis, was observed in both mutant and rescued mice, suggesting that augmentation of FGF signaling is not the sole cause of premature fusion found in this model. The finding that relatively modest augmentation of Smad-dependent BMP signaling leads to premature cranial suture fusion suggests an important contribution of dysregulated BMP signaling to syndromic craniosynostoses, and potential strategies for early intervention.
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DOI：
10.1073/pnas.92.13.6137
发表时间：
1995-06-20
影响因子：
11.1
作者：
LIU, YH;KUNDU, R;MAXSON, RE
通讯作者：
MAXSON, RE
DOI：
10.1359/jbmr.091202
发表时间：
2010-05
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Hiyama A;Gogate SS;Gajghate S;Mochida J;Shapiro IM;Risbud MV
通讯作者：
Risbud MV
影响因子：
6
作者：
Lemonnier, J;Hay, E;Marie, PJ
通讯作者：
Marie, PJ
影响因子：
64.5
作者：
JABS, EW;MULLER, U;MAXSON, R
通讯作者：
MAXSON, R
影响因子：
4.1
作者：
Chen, L;Li, D;Deng, CX
通讯作者：
Deng, CX