The major aims of this proposal are to identify signaling mechanisms initiated by FGFs that underlie normal development of the palate and the midface. Conditional deletion of the two receptors Fgfr1 and Fgfr2 lead to multiple craniofacial defects. Although FGF signaling has been extensively studied from a biochemical standpoint in many laboratories, including our own, remarkably little is known about how these signaling pathways regulate morphogenetic processes in craniofacial development. In this application, we propose: 1. To investigate the pathways regulated by FGF signaling in the palatal epithelium. Loss of Fgfr2 in the epithelium leads to a cleft palate. To establish the signaling mechanisms underlying this defect, we will generate and analyze an allelic series of conditional signaling mouse mutants at the Fgfr2 locus that prevent the binding of single or multiple effector proteins. We will further characterize transcriptional targets of Fgfr2 signaling in the palatal epithelium and determine if they can regulate subsequent proliferation of the underlying mesenchyme. 2. To investigate the pathways regulated by FGF signaling in the neural crest. Loss of Fgfr1 in the neural crest leads to multiple craniofacial defects, including in palate closure. To identify the underlying signaling mechanisms, we will generate and characterize an allelic series of conditional signaling mouse mutants at the Fgfr1 locus that prevent the binding of single or multiple effectors proteins, targeting the same pathways as for Fgfr2. Since the palate and other craniofacial organs are derived from neural crest cells migrated from dorsal neural ectoderm, we will also conduct Cre based lineage analysis to characterize defects in neural crest cell migration that underlie the mutant phenotypes. 3. To identify and characterize the FGF regulated pathways that control frontonasal development. Combined loss of both Fgfr1 and Fgfr2 in neural crest cells leads to facial clefting that extends through the midline. To establish the mechanistic basis for this phenotype, we will perform conditional mutagenesis in neural crest cells with compound Fgfr1 and Fgfr2 conditional mutants carrying point mutations for identical effectors, and compare these to the double null mutants. We will further establish the role of FGF signaling in midface development by conditional mutagenesis specifically in the frontonasal process. The proposed studies are anticipated to have a significant impact in craniofacial biology because they will establish the signaling mechanisms by which FGFs exert their action and open new directions for the prevention of craniofacial birth defects by the possible application of drug targets for critical FGF intracellular effectors.

Public Health Relevance

Craniofacial developmental diseases including cleft lip or palate are the most prevalent birth defects in the human population worldwide. The major aims of this proposal are to identify mechanisms controlled by FGF signaling that underlie normal development of the midface. We will identify downstream FGF intracellular signaling pathways that are critical in midline development, investigate how FGFs signal in the epithelium and in neural crest cells, and analyze the development of the frontonasal process in FGF receptor mutants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE022778-04
Application #
8837606
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2012-07-11
Project End
2016-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Kurowski, Agata; Molotkov, Andrei; Soriano, Philippe (2018) FGFR1 regulates trophectoderm development and facilitates blastocyst implantation. Dev Biol :
Soriano, Philippe (2018) Intersectional gene inactivation: there is more to conditional mutagenesis than Cre. Sci China Life Sci 61:1115-1117
Molotkov, Andrei; Soriano, Philippe (2018) Distinct mechanisms for PDGF and FGF signaling in primitive endoderm development. Dev Biol 442:155-161
Dinsmore, Colin J; Soriano, Philippe (2018) MAPK and PI3K signaling: At the crossroads of neural crest development. Dev Biol :
Molotkov, Andrei; Mazot, Pierre; Brewer, J Richard et al. (2017) Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency. Dev Cell 41:511-526.e4
Brewer, J Richard; Mazot, Pierre; Soriano, Philippe (2016) Genetic insights into the mechanisms of Fgf signaling. Genes Dev 30:751-71
Vasudevan, Harish N; Soriano, Philippe (2016) A Thousand and One Receptor Tyrosine Kinases: Wherein the Specificity? Curr Top Dev Biol 117:393-404
Vasudevan, Harish N; Mazot, Pierre; He, Fenglei et al. (2015) Receptor tyrosine kinases modulate distinct transcriptional programs by differential usage of intracellular pathways. Elife 4:
Brewer, J Richard; Molotkov, Andrei; Mazot, Pierre et al. (2015) Fgfr1 regulates development through the combinatorial use of signaling proteins. Genes Dev 29:1863-74
Fantauzzo, Katherine A; Soriano, Philippe (2015) Receptor tyrosine kinase signaling: regulating neural crest development one phosphate at a time. Curr Top Dev Biol 111:135-82

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