PROJECT I, From Skull Shape to Cell Activity in Coronal Craniosynostosis Craniosynostosis is a common birth defect that can occur as part of a syndrome or as an isolated anomaly. Analysis of skull malformations associated with craniosynostosis disorders often focus on premature closure of vault sutures and change in cranial vault shape. We have novel data from humans and mice that demonstrate that craniosynostosis cranial phenotypes involve all skull bones, sutures other than those of the cranial vault, and cranial soft tissues. To dissect how global alteration of cranial bone and soft tissue development drive craniosynostosis cranial phenotypes, we will quantify the effects of disrupted bone formation in a mouse model at the cellular level using two-photon laser microscopy, combined with a multiscale computational model of skull growth. We will first establish the role of osteoblast lineage cell (OLC) activity in producing specific cranial dysmorphologies through characterization of the temporal and spatial distribution of proliferating and differentiating OLCs in developing mouse skulls. This will be accomplished by developing a new transgenic line, Runx2-RFP, that will be used to generate Osx-GFP;Runx2-RFP mice and two-photon laser microscopy to visualize stages in OLC differentiation during cranial embryogenesis. We will develop a staging system to quantitatively compare OLC proliferation and differentiation patterns in various transgenic lines including mice with coronal craniosynostosis and unaffected littermates (Specific Aim1). This will elucidate the cellular-level changes that occur in cranial development providing the basis for joining cell behavior with 3D shape changes that occur during ontogeny. To rigorously understand how changes in OLC differentiation can give rise to global skull dysmorphology, we will create a multiscale computational model of cranial morphogenesis (Specific Aim 2). The computational modeling approach will enhance a hypothesis driven investigation of the production of craniosynostosis phenotypes constrained by actual, measured parameters. Numbers of cells in initial 'ossification centers', rate of OLC differentiation and proliferation, intracranial pressure gradients from growth induced skull-soft tissue interaction, and rate of suture closure can be parameterized and modified in the model. The results can be continually quantitatively compared to our extensive image archive of bone characteristics and cranial organ shapes in developing mice. Synergy: Interaction between this project and Project III will be based on the differences we detect in OLC proliferation and differentiation patterns in typically developing and craniosynostosis mice as this can contribute directly to knowledge of signaling pathways involved in the spatiotemporal regulation of OLC differentiation to be incorporated in the network analysis of Project III. Precise phenotyping of cranial shapes in mice in which the disease causing mutation is known will inform the morphometric analyses of human craniosynostosis cases accomplished for Project II while the computational model can be used to rule out, or identify the contribution of specific parameters to severity of craniofacial phenotypes in mice, and by extension in humans.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DRG-D)
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Icahn School of Medicine at Mount Sinai
Domestic Higher Education
New York
United States
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Ye, Xiaoqian; Guilmatre, Audrey; Reva, Boris et al. (2016) Mutation Screening of Candidate Genes in Patients with Nonsyndromic Sagittal Craniosynostosis. Plast Reconstr Surg 137:952-61
Singh, Nandini; Dutka, Tara; Reeves, Roger H et al. (2016) Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice. Dev Dyn 245:114-22
Flaherty, Kevin; Singh, Nandini; Richtsmeier, Joan T (2016) Understanding craniosynostosis as a growth disorder. Wiley Interdiscip Rev Dev Biol 5:429-59
Lee, Chanyoung; Richtsmeier, Joan T; Kraft, Reuben H (2015) A computational analysis of bone formation in the cranial vault in the mouse. Front Bioeng Biotechnol 3:24
Weiss, Ken; Buchanan, Anne; Richtsmeier, Joan (2015) How are we made?: Even well-controlled experiments show the complexity of our traits. Evol Anthropol 24:130-6
Trainor, Paul A; Richtsmeier, Joan T (2015) Facing up to the challenges of advancing Craniofacial Research. Am J Med Genet A 167:1451-4
Singh, Nandini; Dutka, Tara; Devenney, Benjamin M et al. (2015) Acute upregulation of hedgehog signaling in mice causes differential effects on cranial morphology. Dis Model Mech 8:271-9
Richtsmeier, Joan T; Jones, Marilyn C; Lozanoff, Scott et al. (2015) The Society for Craniofacial Genetics and Developmental Biology 37th annual meeting. Am J Med Genet A 167:1455-73
Heuzé, Yann; Holmes, Gregory; Peter, Inga et al. (2014) Closing the Gap: Genetic and Genomic Continuum from Syndromic to Nonsyndromic Craniosynostoses. Curr Genet Med Rep 2:135-145
Lee, Chanyoung; Richtsmeier, Joan T; Kraft, Reuben H (2014) A MULTISCALE COMPUTATIONAL MODEL FOR THE GROWTH OF THE CRANIAL VAULT IN CRANIOSYNOSTOSIS. Int Mech Eng Congress Expo 2014: