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.
