Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development
Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development
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DOI：
10.1242/dev.073197
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发表时间：
2012-02-15
期刊：
影响因子：
4.6
通讯作者：
Martin, James F.
中科院分区：
文献类型：
--
作者：
Bonilla-Claudio, Margarita;Wang, Jun;Martin, James F.
我们对脑神经嵴（CNC）中发育、疾病和进化的关键调节因子Bmp 4进行了深入分析。有条件的Bmp 4过表达，使用四环素调节的Bmp 4功能获得性等位基因，导致面部骨骼的变化是最戏剧性的E10.5 Bmp 4诱导后。表达谱分析揭示了Bmp 4诱导基因（BIG）的签名，主要由控制自我更新，成骨细胞分化和负Bmp自动调节的转录调节因子组成。Bmp 2、Bmp 4和Bmp 7的CNC失活实验导致多种CNC衍生的骨骼元素完全或部分丧失，揭示了Bmp信号在膜骨和软骨发育中的关键需求。重要的是，BIG签名在Bmp功能丧失突变体中减少，表明Bmp调节的靶基因受到Bmp剂量的调节。染色质免疫沉淀（ChIP）揭示了BIG特征的一个子集，包括Satb 2、Smad 6、Hand 1、Gadd 4 γ。Gata 3在发育中的下颌骨中与Smad 1/5结合，揭示了Smad直接介导的调节。这些数据支持的假设，BMP信号调节颅面骨骼发育的平衡自我更新和分化途径在CNC祖细胞。
We performed an in depth analysis of Bmp4, a critical regulator of development, disease, and evolution, in cranial neural crest (CNC). Conditional Bmp4 overexpression, using a tetracycline-regulated Bmp4 gain-of-function allele, resulted in facial skeletal changes that were most dramatic after an E10.5 Bmp4 induction. Expression profiling uncovered a signature of Bmp4-induced genes (BIG) composed predominantly of transcriptional regulators that control self-renewal, osteoblast differentiation and negative Bmp autoregulation. The complimentary experiment, CNC inactivation of Bmp2, Bmp4 and Bmp7, resulted in complete or partial loss of multiple CNC-derived skeletal elements, revealing a crucial requirement for Bmp signaling in membranous bone and cartilage development. Importantly, the BIG signature was reduced in Bmp loss-of-function mutants, indicating Bmp-regulated target genes are modulated by Bmp dose. Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including Satb2, Smad6, Hand1, Gadd4 gamma. and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation. These data support the hypothesis that Bmp signaling regulates craniofacial skeletal development by balancing self-renewal and differentiation pathways in CNC progenitors.