The general aims of this project are to determine whether regulation of insulin-like growth factor (IGF) signaling plays an important role in the ability of serotonin (5-HT) to regulate mouse craniofacial development, and to investigate cellular and molecular mechanisms underlying serotonergic regulation of IGF-I and IGF binding protein (IGFBP) gene expression. These studies will focus on IGF signaling because of evidence that IGFs regulate chondrogenesis, and results of recent studies indicating that 5-HT regulates levels of IGF-I and cartilage proteoglycan core protein in embryonic mouse mandibular mesenchyme cultures. Using this culture system, the specific aims are designed to answer the following questions: 1) Does 5-HY regulate deposition of cartilage matrix as well as cartilage core protein expression? Is this regulation of chondrogenesis mediated by IGF-I and its interactions with IGF-I receptors? Are IGFBPs also involved? 2) Does activation of 5-HT receptors alter expression of IGFBPs? 3) Do 5-HT receptors that promote IGF-I and/or IGFBP expression do so by activation of signal transduction cascades leading to phosphorylation of cyclic AMP response element biding proteins (CREBs)? Taken together, these studies will test the working hypothesis that IGF signaling plays an important role in serotonergic regulation of mouse craniofacial development, and will provide insights into cellular and molecular mechanisms underlying regulation of IGF-I/IGFBP gene expression by 5-HT receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE013314-01
Application #
2884877
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Project Start
1999-09-01
Project End
2004-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Levin, Michael; Buznikov, Gennady A; Lauder, Jean M (2006) Of minds and embryos: left-right asymmetry and the serotonergic controls of pre-neural morphogenesis. Dev Neurosci 28:171-85
Bhasin, N; LaMantia, A-S; Lauder, J M (2004) Opposing regulation of cell proliferation by retinoic acid and the serotonin2B receptor in the mouse frontonasal mass. Anat Embryol (Berl) 208:135-43
Polleux, Franck; Lauder, Jean M (2004) Toward a developmental neurobiology of autism. Ment Retard Dev Disabil Res Rev 10:303-17
Buznikov, G A; Lambert, H W; Lauder, J M (2001) Serotonin and serotonin-like substances as regulators of early embryogenesis and morphogenesis. Cell Tissue Res 305:177-86
Lambert, H W; Weiss, E R; Lauder, J M (2001) Activation of 5-HT receptors that stimulate the adenylyl cyclase pathway positively regulates IGF-I in cultured craniofacial mesenchymal cells. Dev Neurosci 23:70-7
Lauder, J M; Wilkie, M B; Wu, C et al. (2000) Expression of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors in the mouse embryo. Int J Dev Neurosci 18:653-62