Craniofacial abnormalities represent a broad and complex class of birth defects and understanding their genetic basis is essential for their diagnosis and treatment. Despite much recent progress in understanding their etiology, many facets of their pathogenesis, which often involves a combination of environmental and genetic factors, remain poorly understood. We have recently identified transcriptional cofactor Jab1 as a novel interacting protein for Runx2, a mater regulator for skeletogenesis. Jab1 is highly conserved with over 60% identity between animal and plant counterparts. It plays essential roles during various developmental processes by modulating other transcription factors function. Jab1 is broadly expressed during embryogenesis including in the chondrocytes and osteoblasts. However, its role in cartilage and bone formation remains mostly unknown. Interestingly, in our preliminary study, loss of Jab1 specifically in chondorcytes with loxP/Cre system led to lethal chondrodysplasia at birth in mice, demonstrating that Jab1 is essential for proper cartilage formation in vivo. Furthermore, deletion of Jab1 specifically in osteo-chondroprogenitor cells results in extremely shortened limbs postnatally. Thus, we hypothesize that Jab1 plays important roles in both embryonic and postnatal skeletogenesis, including craniofacial skeletal development, by modulating the expression of genes involved in cell differentiation, cell proliferation, and apoptosis. Each of our Specific Aims will address specifically the role of Jab1 in craniofacial skeletal development with various mouse genetic and histological tools. Specific Aim 1 will determine the effect of loss of Jab1 specifically in chondrocytes with histological and in situ analysis in Jab1flox/flox;Col2a1-Cre mice. Specific Aim 2 will determine the role of endogenous Jab1 in craniofacial development by deleting Jab1 specifically in neural crest cells with Wnt1-Cre transgenic mice. Specific Aim 3 will determine the function of Jab1 in postnatal endochondral ossification with Col2a1-Cre-ER transgenic lines to induce the Jab1 deletion postnatally in a temporally controlled manner and study its effect on craniofacial morphogenesis and growth plate formation. Overall, this study will further our understanding of the genetic factors affecting craniofacial development and also generate useful mutant mouse models for craniofacial defect and chondrodysplasia research. PUBLIC HEALTH RELEVANCE: Transcriptional co-factor Jab1 plays essential roles during normal development and tumorigenesis by modulating the functions of other transcription factors. Therefore, a better understanding of the role of Jab1 in skeletogenesis, especially craniofacial development, will provide us an important insight into the molecular and genetic basis of craniofacial abnormalities and chondrodysplasia.