Phenotypic variation is a hallmark of craniofacial birth defects, but understanding the relationship between variable morphology and disease remains elusive. In this work we propose to test a model that may explain phenotypic variation within similar genotypes. This model is based on our preliminary data showing a nonlinear relationship between Sonic hedgehog (SHH) signaling and continuous phenotypic variation in the face. We hypothesize that small changes in SHH pathway activity produce large phenotypic changes that have increased variance due to heterogeneous cellular responses to compromised pathway activity. In the first Specific Aim of this grant we will focus on examining the extent to which nonlinear SHH signaling contributes to variation in cellular response. This will be done at the population and the individual cell level. In the Second and Third Specific Aims we will turn our attention to in vivo genetic models of graded SHH signaling. We will examine the phenotype of resulting embryos and we will determine the variance of the phenotypes. Our model predicts that as the nonlinearity in SHH signaling increases the potential to produce large variance also increases. The experiments designed in this application will directly test this prediction and will illuminate a potentially important mechanism that destabilizes complex developmental systems. The use of quantitative analyses such as, geometric morphometrics coupled with quantitative cellular assays and quantitative PCR, throughout this grant gives us the power to perform the analyses proposed in this application.
Structural malformations of the face are common and often exhibit a large degree of morphologic variation;however, the mechanisms underlying variation are not known. Our objective is to test a model based on nonlinearities of molecular signaling that may produce large phenotypic variance. This basic research will help explain one of the most enigmatic features of human disease and will allow more in depth mechanistic explorations of potential therapeutic targets.
|Young, Nathan M; Linde-Medina, Marta; Fondon, John W et al. (2017) Craniofacial diversification in the domestic pigeon and the evolution of the avian skull. Nat Ecol Evol 1:95|
|Green, Rebecca M; Leach, Courtney L; Hoehn, Natasha et al. (2017) Quantifying three-dimensional morphology and RNA from individual embryos. Dev Dyn 246:431-436|
|Percival, Christopher J; Liberton, Denise K; Pardo-Manuel de Villena, Fernando et al. (2016) Genetics of murine craniofacial morphology: diallel analysis of the eight founders of the Collaborative Cross. J Anat 228:96-112|
|Young, Nathan M; Sherathiya, Krunal; Gutierrez, Luis et al. (2016) Facial surface morphology predicts variation in internal skeletal shape. Am J Orthod Dentofacial Orthop 149:501-8|
|Pavli?ev, Mihaela; Mitteroecker, Philipp; Gonzalez, Paula M et al. (2016) Development Shapes a Consistent Inbreeding Effect in Mouse Crania of Different Line Crosses. J Exp Zool B Mol Dev Evol 326:474-488|
|Gonzalez, Paula N; Gasperowicz, Malgorzata; Barbeito-Andrés, Jimena et al. (2016) Chronic Protein Restriction in Mice Impacts Placental Function and Maternal Body Weight before Fetal Growth. PLoS One 11:e0152227|
|Gonzalez, P N; Pavlicev, M; Mitteroecker, P et al. (2016) Genetic structure of phenotypic robustness in the collaborative cross mouse diallel panel. J Evol Biol 29:1737-51|
|Smith, Francis J; Percival, Christopher J; Young, Nathan M et al. (2015) Divergence of craniofacial developmental trajectories among avian embryos. Dev Dyn 244:1158-1167|
|Young, Nathan M; Capellini, Terence D; Roach, Neil T et al. (2015) Fossil hominin shoulders support an African ape-like last common ancestor of humans and chimpanzees. Proc Natl Acad Sci U S A 112:11829-34|
|Petryk, Anna; Graf, Daniel; Marcucio, Ralph (2015) Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans. Wiley Interdiscip Rev Dev Biol 4:17-32|
Showing the most recent 10 out of 28 publications