Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling

摘要 颅缝早闭是一种使人衰弱的疾病，其特征是过早的颅缝融合， 头骨形状异常颅缝早闭症的估计患病率为1：2，500活产，使其成为世界上最严重的颅缝早闭症之一。 影响骨骼系统的最普遍的先天性畸形。唯一的治疗方法是广泛的， 经常是多次的重建手术母体R 01的长期目标是定义分子 BMP信号传导成分的功能获得性突变导致颅缝早闭的机制 啮齿动物模型。我们已经建立了一个条件性小鼠模型，它显示出增强的神经嵴特异性 颅骨和骨缝中通过BMP 1型受体BMPR 1A的BMP信号传导。这种模式是独特而重要的 这是由于：1）观察到p53诱导的细胞凋亡的上调，以及2）异位软骨形成于 融合早于过早融合，提示颅缝早闭不是一种骨病，而是干细胞疾病。 我们最近的数据有力地表明，增强的BMP-Smad信号传导活动影响细胞的命运 通过mTOR信号传导将多能神经嵴前体向软骨形成谱系特化 和Wnt典型信号传导活性。在这份行政补充文件中，我们提出了一项新的合作计划， 与密歇根大学医学院的Jason Spence博士一起直接解决细胞和分子 BMP信号的增加如何改变颅神经嵴细胞的细胞命运的机制。我们将 利用培养物中单细胞衍生的球体形成和三维类器官形成来直接测量 来自早期胚胎的原代神经嵴细胞以及来自 神经嵴因此，这项合作的结果将为分子靶点提供更好的见解， 恢复正常的细胞命运决定能力，从而对人类病例进行潜在的治疗。

ABSTRACT Craniosynostosis is a debilitating condition characterized by premature cranial suture fusion resulting in abnormal skull shape. The estimated prevalence of craniosynostosis is 1:2,500 live births making it one of the most prevalent congenital malformations affecting the skeletal system. The only treatment is extensive, and often multiple, reconstructive surgeries. The long-term goal of the parent R01 is to define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis in the rodent models. We have established a conditional mouse model, which shows enhanced neural crest-specific BMP signaling via BMP type 1 receptor BMPR1A in the skull and sutures. This model is unique and important due to: 1) upregulation of p53-induced apoptosis is observed, and 2) ectopic cartilage is formed at the site of fusion prior to premature fusion, suggesting that craniosynostosis is not a bone disease but stem cell disease. Our recent data strongly suggest that augmented BMP-Smad signaling activities influences cell fate specification of multi-potent neural crest precursors towards chondrogenic lineage through mTOR signaling and Wnt canonical signaling activities. In this Administrative Supplements, we propose a new collaboration with Dr. Jason Spence at the University of Michigan Medical School to directly address cellular and molecular mechanisms of how increased BMP signaling alters cell-fate specification in cranial neural crest cells. We will use single cell derived sphere formation and 3-dimentional organoid formation in culture to directly measure multi-potency of primary neural crest cells from early stage embryos as well as established stem cell lines from neural crests. Results from this collaboration will therefore provide better insights for molecular targets to restore normal cell fate determination ability and thus potential therapeutic treatment of human cases.