ROLE OF LDB1-LMX1B TRANSCRIPTION FACTOR COMPLEX IN CALVARIA DEVELOPMENT

描述（由申请人提供）：颅骨（颅骨的上部）由骨板和纤维关节（缝合线和囟门）组成，两者之间的平衡对颅骨的正常发育至关重要。颅骨畸形是人类最常见的先天缺陷之一；颅缝闭合（缝合线过早丢失）会导致颅骨畸形，也会影响大脑和口面部发育。目前颅缺损的治疗往往涉及侵入性和重复性手术，并发症风险较高，因此改进干预方法势在必行。全面了解颅发育的分子遗传调控对于设计诊断、治疗和预防相关出生缺陷的创新方法至关重要。我们研究的长期目标是通过识别这一过程的重要因素并确定它们之间的关系来表征颅发育的基因调控网络。根据我们的初步结果，LDB1 （lim结构域结合蛋白1）是一种转录辅助因子，在颅骨发育中起重要作用；失活

DESCRIPTION (provided by applicant): The calvaria (upper part of the skull) comprises plates of bone and fibrous joints (sutures and fontanelles), and the balance between the two components is essential for normal development of the calvaria. Calvarial malformation is among the most common birth defects in humans; craniosynostosis (premature loss of suture(s)) leads to a dysmorphic skull and can also affect brain and orofacial development. Current treatment of calvarial defects often involves invasive and repetitive surgeries with relatively high risks for complications, and thus improving the methods of intervention is imperative. Comprehensive understanding of the molecular genetic regulation of calvaria development is crucial to devising innovative methods for diagnosis, treatment, and prevention of related birth defects. The long-term goal of our research is to characterize the gene regulatory network of calvaria development, by identifying factors important for this process and determining their relationship. Based on our preliminary results, LDB1 (LIM-domain binding protein 1), a transcription cofactor, plays an essential role in calvaria development; inactivation of Ldb1 in head mesenchyme and some of the surrounding tissues in mice led to ectopic bone formation at the vertex in place of a fontanelle and parts of the sutures, mimicking craniosynostosis. In addition, an earlier report showed a similar defect in mouse mutants of human Nail-Patella syndrome gene, Lmx1b (LIM homeobox transcription factor 1b), which suggests that LDB1 and LMX1B may be partners in this context. However, molecular and cellular mechanisms by which Ldb1 and Lmx1b regulate calvaria development remain unknown. Therefore, the goal of this research proposal is i) to characterize the function of Ldb1 in calvari development, and ii) determine whether Lmx1b is indeed the partner of Ldb1 for this specific role. We will use mouse mutant models as well as cell culture and organ culture systems to determine the morphological, cellular and molecular changes resulting from the mutation of Ldb1 and Lmx1b. The outcome of this research will provide novel insights into the genetic regulation of calvaria development, and establish Ldb1 and Lmx1b as important players in human calvarial birth defects such as craniosynostosis.