Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling

描述（由申请人提供）：颅缝闭闭是一种以颅缝过早融合为特征的衰弱性疾病，导致颅骨形状异常，失明和智力迟钝。颅缝闭闭的患病率是1在2,500活产，这是骨骼系统的先天性畸形发病率最高的一个。拟议研究的长期目标是确定BMP信号成分的功能获得突变导致颅缝闭锁的分子机制。最近的研究表明，颅缝闭锁与FGF信号成分Twist、Msx2和Efnb1的突变有关，然而，大多数（70%）颅缝闭锁的遗传原因尚不清楚。最近有人提出BMP信号与颅缝闭合有关。我们开发了一种新的小鼠颅缝闭合模型，其特征是通过BMP信号成分的功能获得突变使异位缝合线过早融合。该模型是独特而重要的，因为1)观察到FGF信号上调，2)融合前在融合部位形成异位软骨，3)在BMPRIA杂合零背景下恢复表型，表明精确控制BMP信号对于防止颅缝闭锁至关重要。我们将使用这个模型来研究导致发病的分子机制。我们的研究将进一步明确直接参与颅缝过早融合导致颅缝闭锁发病机制的分子途径，从而为治疗人类病例的潜在分子靶点提供更好的见解。

DESCRIPTION (provided by applicant): Craniosynostosis is a debilitating condition characterized by premature cranial suture fusion, resulting in abnormal skull shape, blindness and mental retardation. The prevalence of craniosynostosis is at 1 in 2,500 live births, which is one of the highest incidences of congenital malformation of skeletal system. The long-term goal of the proposed studies is to define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Recent studies demonstrated that craniosynostosis is associated with mutations in FGF signaling components, Twist, Msx2 and Efnb1, however, genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling to craniosynostosis is recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of a metopic suture by a gain-of-function mutation in a BMP signaling component. This model is unique and important because 1) upregulation of FGF signaling is observed, 2) ectopic cartilage is formed at the site of fusion prior to the fusion, and 3) the phenotype is rescued in heterozygous null background of BMPRIA, indicating that the precise control of BMP signaling is critical to prevent craniosynostosis. We will use this model to investigate molecular mechanisms by which leads to pathogenesis. Our study will further define molecular pathways directly involves in pathogenesis of premature fusion of cranial sutures leading to craniosynostosis, and will therefore provide better insights for potential molecular targets for therapeutic treatment of human cases. PUBLIC HEALTH RELEVANCE: In this proposal, we will define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling to craniosynostosis is recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of a metopic suture by a gain-of- function mutation in a BMP signaling component. We will use this model to investigate molecular mechanisms by which leads to pathogenesis. Our study will further define molecular pathways directly involves in pathogenesis of premature fusion of cranial sutures leading to craniosynostosis, and will therefore provide better insights for potential molecular targets for therapeutic treatment of human cases.