Development of the middle and upper face rely on signaling interactions among the forebrain, the neural crest mesenchyme, and the surface ectoderm. We have determined that signals derived from the forebrain control the formation of a signaling center (Frontonasal ectodermal zone; FEZ) in the surface ectoderm that regulates growth and patterning of the middle and upper face. Further, we demonstrated that disruptions to FEZ formation produced embryos that exhibited formes frustes of Holoprosencephaly (HPE). Our long term goal is to determine the underlying molecular mechanism(s) that regulate the establishment of the FEZ and to determine how signals derived from this signaling center regulate patterned growth of the middle and upper face. Cells within the FEZ express morphogens like Shh, Fibroblast growth factor 8 (Fgf8), and Bone morphogenetic proteins (Bmps). These molecules are ideal candidates for mediating function of the FEZ and are likely targets for teratogenic insults that produce malformations within this region of the head. We hypothesize that signaling by BMPs and SHH regulate induction of Shh expression in the ectoderm, and that together, Bmps, Shh, and Fgf8 regulate function of the FEZ. In our first Specific Aim we will assess whether BMP and/or SHH signaling are directly required within the ectodermal cells for induction of Shh expression in the FEZ, and we will assess the functional consequence of FEZ formation in the absence of BMP signaling. The objective of the second Specific Aim is to examine the role of the Bmps that are expressed within the FEZ using a tissue-specific, loss-of-function approach in avian embryos. Specifically, we will assess the morphological and molecular consequence of knocking-down Bmp expression. In our third Specific Aim we will assess the role of Fgf8 in establishing the FEZ, and the role of Fgf8 in mediating the function of this signaling center. We will use genetic approaches to ablate or reduce Fgf8 expression in the forebrain and ectoderm of mouse embryos and we will assess formation of the FEZ. Additionally, to distinguish between early and late roles of Fgf8 in FEZ function, we will characterize each FEZ in a novel chimeric system. Our results will contribute to the overall understanding of the epithelial-mesenchymal interactions that regulate development of the middle and upper face and will provide a basis to understand how defects in this region arise. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE018234-01
Application #
7249157
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2007-06-01
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$384,896
Indirect Cost
Name
University of California San Francisco
Department
Orthopedics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
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
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
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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