Phenotypic variation is a hallmark of craniofacial birth defects, but understanding the relationship between variable morphology and disease remains elusive. The difficulty in defining the basis for variable morphology occurs because of the multitude of genetic factors that influence facial morphology. However, the molecular pathways that regulate facial form are likely to converge on a smaller set of cellular processes. In this work, we focus on two cellular processes that control growth of the facial primordia, because differences in growth contribute to variation in phenotype. We hypothesize that by discretely altering molecular signaling pathways that regulate patterning of the major axes of the upper jaw continuous phenotypic variation will be produced due to altered patterns of gene expression that ultimately control cell proliferation and apoptosis. In each Aim we will focus on the relationship among cell proliferation, signaling by specific molecular pathways, and morphology. In the Third Specific Aim we will turn our attention to examine the relationship among cell death, cell survival, signaling, and morphology.
In Aim 1 we will disrupt signals form the brain that control proliferation of neural crest cells.
In Aim 2 we will disrupt signals within the neural crest mesenchyme that regulate cell proliferation.
In Aim 3 we will disrupt signals from the brain and within the neural crest that regulate apopotosis and cell proliferation. In each Aim we will use 3-D and 2-D morphometrics to quantify morphologic changes in the brain and face, and we will correlate these changes with activation of specific molecular pathways, expression of signaling molecules, receptors, and transcription factors that control cell proliferation and survival, and cell proliferation and cell death. In each aim, we propose biochemical or cell- based experiments to ameliorate the phenotypic changes induced by our treatments and directly test the mechanisms that underlie production of altered morphology. These experiments will be evaluated using morphometric analysis, because this approach allows us to objectively and systematically evaluate our interventions. Overall, this work will allow us to quantitatively assess the role of growth in production of morphologic variation during development of the face. This approach will allow investigators to bridge work on specific genetic disruptions with molecular changes and cellular processes that regulate facial form. Further, with the advent of high resolution in utero imaging methods, our research will create a basis for developing parameters that allow earlier detection of facial malformations and may lead the way to in utero treatments.
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 examine cellular processes that affect growth in order to assess morphologic variation in normal and diseased populations. This basic research will help develop metrics for better in utero diagnostics and eventual treatments of structural birth defects of the face.
| Hallgrimsson, Benedikt; Green, Rebecca M; Katz, David C et al. (2018) The developmental-genetics of canalization. Semin Cell Dev Biol : |
| Percival, Christopher J; Green, Rebecca; Roseman, Charles C et al. (2018) Developmental constraint through negative pleiotropy in the zygomatic arch. Evodevo 9:3 |
| Linde-Medina, Marta; Marcucio, Ralph (2018) Living tissues are more than cell clusters: The extracellular matrix as a driving force in morphogenesis. Prog Biophys Mol Biol 137:46-51 |
| 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; Marangoni, Pauline; Tapaltsyan, Vagan et al. (2017) The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape. G3 (Bethesda) 7:1439-1450 |
| 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; Fish, Jennifer L; Young, Nathan M et al. (2017) Developmental nonlinearity drives phenotypic robustness. Nat Commun 8:1970 |
| Linde-Medina, M (2016) Testing the cranial evolutionary allometric 'rule' in Galliformes. J Evol Biol 29:1873-8 |
| Linde-Medina, Marta; Hallgrímsson, Benedikt; Marcucio, Ralph (2016) Beyond cell proliferation in avian facial morphogenesis. Dev Dyn 245:190-6 |
| 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 |
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