Craniosynostosis is a common birth defect that can occur as part of a syndrome or as an isolated anomaly. Though often defined as the premature closure of a cranial vault suture, anatomic and clinical studies reveal complex dysmorphology of the entire head. One complex trait typical of craniosynostosis syndromes is 'midfacial hypoplasia', a catch-all diagnosis that is defined on the basis of deficient development of the upper jaw, nasopharynx, and cheekbones presenting with a flatter than average face and associated respiratory difficulties. We have novel data from humans and mouse models of craniosynostosis which detail precise aspects of the cranial vault, cranial base, facial skeleton, facial sutures, and upper airway that are differentially affected by various FGFR2 and FGFR3 mutations. We hypothesize that the generalized condition of 'midfacial hypoplasia'represents a complex phenotype whose component parts differ depending upon the specific mutation. Relatively little is known about how the mutations identified as causative in craniosynostosis affect cells and tissues of the developing craniofacial complex to result in midfacial and choanal hypoplasia or atresia. In this project, we will perform quantitative analysis of 3D image data from human craniosynostosis phenotypes to formulate and test hypotheses pertaining to localized effects of various mutations in mouse models with craniosynostosis. We will use conditional mutant mice including Fgfr2+/S252W and Fgfr2+/P253R Apert syndrome, Fgfr2cC342Y/+ Crouzon/Pfeiffer syndrome, and Fgfr3+/P244R Muenke syndrome, and Wnt1-, Mesp1- and Sox17-2A-I-Cre-reporter mice to quantitatively study the differential effects of these mutations on specific craniofacial structures and cells and tissues that are derived from diverse embryonic tissues and that contribute to 'midfacial hypoplasia'. Once these precise phenotypic effects are defined on facial and cranial base phenotypes, we will analyze the role of these mutations on cell migration, differentiation, apoptosis, and proliferation. Finally, using RNA-seq, in situ hybridization, immunoblots, and immunohistochemistry on tissues micro-dissected from specific regions and developmental stages, we will scrutinize candidate Fgfr pathways (e.g., Erk1/2, p38) and identify novel pathways. We will provide essential information on dysmorphogenesis of the upper airway and face and establish objective criteria for the definition of midfacial and choanal hypoplasia needed to improve healthcare for numerous patients with these conditions.

Public Health Relevance

Midfacial hypoplasia, a general term that describes a disproportionately small face, is a common feature of many craniofacial diseases including craniosynostosis syndromes. Midfacial hypoplasia involves developmental defects of various skeletal components and/or soft tissue organs and spaces such as the upper airway. We will use 3D data from craniosynostosis patients to quantitatively define these abnormalities and to guide investigations in mouse models to determine the underlying molecular, cellular and developmental basis of these disorders. Through these studies we will ultimately gain insights to improve care of patients with these conditions.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-A (02))
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Scholnick, Steven
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Pennsylvania State University
Social Sciences
Schools of Arts and Sciences
University Park
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
Holmes, Greg; van Bakel, Harm; Zhou, Xueyan et al. (2015) BCL11B expression in intramembranous osteogenesis during murine craniofacial suture development. Gene Expr Patterns 17:16-25
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
Starbuck, John M; Dutka, Tara; Ratliff, Tabetha S et al. (2014) Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice. Am J Med Genet A 164A:1981-90

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