Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling

摘要 颅缝融合是一种衰弱的情况，其特征是过早的颅缝融合导致 头骨形状异常。据估计，颅缝早闭的患病率为1：2,500活产儿，使其成为 最常见的影响骨骼系统的先天畸形。唯一的治疗方法是广泛的，而且 通常是多次的重建手术。亲本R01的长期目标是定义分子 骨形态发生蛋白信号成分的功能获得突变导致颅性融合的机制 啮齿动物模型。我们已经建立了一个条件性小鼠模型，该模型显示了增强的神经脊特异性 骨形态发生蛋白通过骨形态发生蛋白1型受体BMPR1a在颅骨和骨缝中的信号传导。这种模式是独一无二的，也是重要的 由于：1)P53诱导的细胞凋亡上调，2)异位软骨形成于 早融合先于融合，提示颅缝早闭不是骨病，而是干细胞病。 我们最近的数据有力地表明，增强的BMP-Smad信号活动影响细胞命运 MTOR信号转导多能神经脊前体向成软骨细胞谱系的规范 和Wnt规范信号活动。在本《管理补充资料》中，我们提出了新的协作方案 与密歇根大学医学院的杰森·斯宾塞博士一起直接研究细胞和分子 骨形态发生蛋白信号增加如何改变脑神经脊细胞中细胞命运的机制。我们会 利用培养中的单细胞衍生球形成和三维有机体形成直接测量 来自早期胚胎的原代神经脊细胞以及已建立的胚胎干细胞系的多能性 神经顶峰。因此，这种合作的结果将为分子靶标提供更好的洞察力 恢复正常的细胞命运决定能力，从而有可能治疗人类病例。

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.