Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling

摘要

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.