Phenogenetics of Skull and Brain Integration in Craniosynostosis

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DESCRIPTION (provided by applicant): Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation occurring in 1 out of every 2500 live births, and shows marked variation of cranial phenotypes. The parent R01 (R01-DE018500) proposed a unifying study of molecular and morphological data aimed at identifying intermediate developmental steps in the genotype-phenotype continuum of craniosynostosis. We are testing developmental associations between skull and brain using 3D data from micro-CT and micro-MR images of the Fgfr2+/S252W and Fgfr2cC342Y/+ mouse models for Apert and Crouzon syndromes, respectively. Using anatomical sites identified by our investigations of human skull and brain, as well as patterns of brain and skull covariation identified in our analyses of these mouse models as a temporal and spatial guide, we will document patterns of abnormal proliferation, differentiation, apoptosis, and Fgf/Fgfr signaling in developing cranial tissues of mutant mice at three developmental stages. Our hypothesis is that the spatiotemporal map of abnormal Fgf/Fgfr signaling in formative skull and brain is the basis for a series of developmental events that result in anomalous cellular processes local to those sites and ultimately result in the abnormal head and brain shape in craniosynostosis. We have important preliminary results on inbred mice with a Fgfr2+/P253R mutation, the orthologous mutation occuring in one third of Apert syndrome patients. Our preliminary data suggest that although the S252W and P253R mutations occur in adjacent amino acids, each mutation is associated with statistically different brain and skull phenotypes. We quantify increased variation in coronal suture closure in P0 mice carrying the Fgfr2+/P253R mutation and document a relationship between this variation and the pattern of covariation between brain and skull 3D morphology in both models. Our goal is to uncover the developmental rules of brain-skull relationships that contribute to suture patency. This can be most efficiently accomplished by adding mice carrying the Fgfr2+/P253R mutation to our resaserch design. In response to Notice Number (NOT-OD-09-058) and Notice title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications, we add to our investigations the Fgfr+/P253R Apert mouse, that was not developed until after the parent R01 application was submitted. We propose to study the phenogenetics of the Fgfr+/P253R Apert mouse using the same methods of analysis proposed in the parent R01 application that received a percentile of 0.2, and to compare results among these three mouse models that are bred on the same genetic background. Our morphological analyses will inform our molecular investigations of how the two Apert syndrome mutations, and the three different Fgfr2 mutations, compare in their phenogenetic processes to produce developmental relationships that lead to craniosynostosis phenotypes. PUBLIC HEALTH RELEVANCE: Craniosynostosis is a common malformation which is defined by the premature fusion of skull bones, most commonly those of the calvaria. Our aims are to study the integrated nature of skull and brain development in craniosynostosis using data from human populations with nonsyndromic coronal craniosynostosis and Apert, Crouzon and Pfeiffer syndrome, as well as data from mouse models for Apert syndrome to understand the development of the entire head in these disorders and not just the closed suture.