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.
Abnormalities in the calvaria (upper part of the skull) are a major class of birth defects in humans. The proposed project will provide novel insights into the molecular genetic regulation of calvaria development, which can contribute to devising innovative methods for diagnosis, treatment, and prevention of cavlaria- related birth defects.
|Cesario, Jeffry M; Landin Malt, André; Chung, Jong Uk et al. (2018) Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria. Dev Biol 443:103-116|