The proposed studies will test the working hypothesis that the neurotransmitter serotonin (5-HT) acts as a morphogenetic signal during craniofacial development by activation of specific receptors and signal transduction mechanisms that regulate cell proliferation, migration and expression of other morphoregulatory molecules. Serotonergic regulation of two growth factors (S-100beta, IGF-II) and the adhesion-related molecule tenascin will be investigated in mandibular micromass cultures and explants using quantitative in situ hybridization and immunobinding assays, and compared to cartilage core protein, a marker of chondrogenesis. Effects on morphogenesis of structures expressing 5-HT receptors and morphoregulatory molecules (e.g., Meckel's cartilage, tooth germ) will be studied in mandibular explants. Mechanisms underlying the dose-dependent stimulatory effects of 5-HT on migration of cranial neural crest will be studied using an established cell migration assay. The ability of selective receptor agonists to promote migration will be compared to effects on neural crest expression of S-100beta (a calcium binding protein) and tenascin. Serotonergic regulation of cell prolIferation and second messengers in neural crest and mandibular cultures will be determined using 3H-thymidine incorporation, cAMP, and PI hydrolysis assays. These studies are relevant to the etiology of Down's syndrome where characteristic craniofacial malformations occur, levels of S-100beta and IGF-II are elevated, and Serotonergic mechanisms are altered. This work may also provide information regarding the teratogenic potential of Serotonergic drugs during pregnancy.
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