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Growth Factor Signaling and Craniofacial Development

生长因子信号传导和颅面发育

基本信息

批准号：
9981416
负责人：
Philippe M Soriano
金额：
$ 59.86万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981416
关键词：
Affect Area Binding Sites Biology Biosensor Cell Differentiation process Cell Proliferation Cells Cephalic Cleft Palate Cleft lip with or without cleft palate Complex Congenital Abnormality Craniofacial Abnormalities Development Embryo Face Fibroblast Growth Factor Genes Genetic Transcription Goals Growth Factor Human Immediate-Early Genes Individual Kinetics Link Location MEKs Mesenchyme Molecular Morphogenesis Mus Mutagenesis Mutant Strains Mice Mutation Neural Crest Neural Crest Cell Osteoblasts Output PC12 Cells Pathway interactions Phenotype Platelet-Derived Growth Factor Population Prevention Process Receptor Protein-Tyrosine Kinases Role Serum Response Factor Signal Pathway Signal Transduction Site Work cleft lip and palate combinatorial craniofacial craniofacial development developmental disease experimental study gene induction genetic analysis in vivo inhibitor/antagonist mutant myocardin new technology novel programs receptor response transcription factor

项目摘要

The major aims of this proposal are to identify signaling mechanisms underlying midface development that are controlled by PDGF and FGF. Loss of the Pdgfra or Fgfr1 receptors leads to facial clefting and improper development of the frontonasal process, whereas hypomorphic mutations in these pathways result in cleft palate. Pdgfra and Fgfr1 regulate craniofacial development mainly in cranial neural crest cells (cNCCs) through PI3K and Erk, respectively. PDGF induces a short duration or Erk signaling cell differentiation, whereas FGF promotes cell proliferation and perdurance of the Erk signal. Last, PDGF and FGF regulate craniofacial development by engaging immediate early genes (IEGs) through serum response factor (Srf), a critical transcription factor activated by these growth factors itself required for midface closure. This application proposes: 1. To establish the roles and locations of PI3K and Erk signaling in craniofacial development. We will analyze midface development in conditional PI3K and Erk core component genes in NCCs. To identify sites of PDGF and FGF driven signaling activity in vivo, we will breed PI3K and Erk biosensors into wild type, Pdgfr and Fgfr mutant backgrounds. 2. To determine how PDGF and FGF signaling differences differentially regulate craniofacial development. We will alter the duration of Erk signaling in primary MEPMs using Mek/Erk and PKC inhibitors, and investigate how this affects cell differentiation and proliferation. To establish the relative importance of combinatorial vs. dynamic signaling and downstream responses in craniofacial development, we will analyze expression of known PDGF and FGF transcriptional targets that are PI3K and Erk dependent and linked to differentiation or proliferative responses, in Pdgfr/PI3K or Fgfr/Erk neural crest specific mutants. 3. To determine the signaling mechanisms through which Srf, a shared PDGF and FGF transcriptional target, regulates differential transcriptional outputs. Srf interacts with two classes of co-factors, Myocardin Related Transcription Factors (MRTFs) or Ternary Complex Factors (TCFs). PDGF promotes the association of Srf with MRTFs through PI3K to regulate the expression of cytoskeletal target genes critical for craniofacial development, whereas both PDGF and FGF allow Srf to interact with TCFs through PI3K and Erk signaling to facilitate the expression of core IEGs. To establish the molecular pathways and targets by which growth factors regulate midface development through Srf, we will generate mice carrying mutations in Srf that abrogate its ability to associate with MRTFs, while maintaining its interactions with TCFs. These proposed studies explore novel territories in the area of growth factor signaling in craniofacial biology and open new directions for the prevention of craniofacial birth defects.

本提案的主要目的是确定中面发育的信号机制