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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD078233-05
Application #
9657563
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Richtsmeier, Joan T (2018) A century of development. Am J Phys Anthropol 165:726-740
Holmes, Greg; Zhang, Lening; Rivera, Joshua et al. (2018) C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model. PLoS One 13:e0201492
Martínez-Abadías, Neus; Mateu Estivill, Roger; Sastre Tomas, Jaume et al. (2018) Quantification of gene expression patterns to reveal the origins of abnormal morphogenesis. Elife 7:
Musy, Marco; Flaherty, Kevin; Raspopovic, Jelena et al. (2018) A quantitative method for staging mouse embryos based on limb morphometry. Development 145:
Holmes, Greg; O'Rourke, Courtney; Motch Perrine, Susan M et al. (2018) Midface and upper airway dysgenesis in FGFR2-related craniosynostosis involves multiple tissue-specific and cell cycle effects. Development 145:
Lesciotto, Kate M; Heuzé, Yann; Jabs, Ethylin Wang et al. (2018) Choanal Atresia and Craniosynostosis: Development and Disease. Plast Reconstr Surg 141:156-168
Motch Perrine, Susan M; Stecko, Tim; Neuberger, Thomas et al. (2017) Integration of Brain and Skull in Prenatal Mouse Models of Apert and Crouzon Syndromes. Front Hum Neurosci 11:369
Wilkie, Andrew O M; Johnson, David; Wall, Steven A (2017) Clinical genetics of craniosynostosis. Curr Opin Pediatr 29:622-628
Starbuck, John M; Cole 3rd, Theodore M; Reeves, Roger H et al. (2017) The Influence of trisomy 21 on facial form and variability. Am J Med Genet A 173:2861-2872
Lee, Chanyoung; Richtsmeier, Joan T; Kraft, Reuben H (2017) A COMPUTATIONAL ANALYSIS OF BONE FORMATION IN THE CRANIAL VAULT USING A COUPLED REACTION-DIFFUSION-STRAIN MODEL. J Mech Med Biol 17:

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