The goal of our first cycle of funding was to examine the molecular mediators of tissue interactions that regulate craniofacial development. We focused on the role that the brain plays in establishing a signaling center, the Frontonasal Ectodermal Zone (FEZ), because the FEZ regulates patterned growth of the upper jaw. Our research revealed that the brain controls the spatial organization of the FEZ, which then produces unique facial morphologies including disease phenotypes that fall along a continuous spectrum of morphologies. Our preliminary data suggest a novel mechanism by which the brain controls the spatial organization of the FEZ. These data also indicate that the FEZ is dynamic and shifts expression boundaries to regulate multiple morphogenetic processes during facial development. Finally, cellular responses to Fgf signaling during facial development have been largely unknown, and our preliminary studies suggest that basic cellular processes are controlled by FGF signaling. In response to FGF signaling these cellular behaviors participate in regulating facial morphogenesis. Collectively, these data suggest mechanisms that are used for development, integration, and fusion of facial primordia. Based on these data, we hypothesize that SHH from the brain controls facial morphogenesis by inducing a negative feedback loop in the FEZ via microRNAs and this helps to define the domain of Shh in the FEZ. The FEZ then orchestrates its own changing expression domain to control morphogenetic processes such as proliferation, migration, and polarization of mesenchymal cells that drive growth and fusion of the facial primordia that form the upper jaw. We will test this hypothesis in three Specific Aims. First, we will examine the extent to which these micro RNAs regulate the spatial organization of Shh expression in the FEZ and validate putative target genes. Second, the FEZ changes shape over time, and we will determine the role that novel expression domains of Shh play during growth and fusion of the median nasal, lateral nasal, and maxillary processes. Third, we will examine the role that downstream targets of FGF signaling have in mediating the cellular response to signaling by this pathway, and we will examine a mouse model of Crouzon Syndrome. The results from this research will lead to a more comprehensive understanding of mechanisms that control facial development and will identify putative disease causing mechanisms related to cleft lip and palate among other structural disease.

Public Health Relevance

Structural malformations of the face are common, but the underlying mechanisms causing disease are relatively unknown. Our objective is to examine the molecular basis of the tissue interactions that regulate facial development in order to advance our understanding of disease mechanisms and aid development of in utero diagnostics and eventual treatments of structural birth defects of the face.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Scholnick, Steven
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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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
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
Hibberd, Christine E; Bowdin, Sarah; Arudchelvan, Yamini et al. (2016) FGFR-associated craniosynostosis syndromes and gastrointestinal defects. Am J Med Genet A 170:3215-3221
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
Hu, Diane; Young, Nathan M; Xu, Qiuping et al. (2015) Signals from the brain induce variation in avian facial shape. Dev Dyn 244:1133-1143
Xu, Qiuping; Jamniczky, Heather; Hu, Diane et al. (2015) Correlations Between the Morphology of Sonic Hedgehog Expression Domains and Embryonic Craniofacial Shape. Evol Biol 42:379-386
Lainoff, Alexis J; Moustakas-Verho, Jacqueline E; Hu, Diane et al. (2015) A comparative examination of odontogenic gene expression in both toothed and toothless amniotes. J Exp Zool B Mol Dev Evol 324:255-69
Hu, Diane; Young, Nathan M; Li, Xin et al. (2015) A dynamic Shh expression pattern, regulated by SHH and BMP signaling, coordinates fusion of primordia in the amniote face. Development 142:567-74
Griffin, John N; Compagnucci, Claudia; Hu, Diane et al. (2013) Fgf8 dosage determines midfacial integration and polarity within the nasal and optic capsules. Dev Biol 374:185-97

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