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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD022052-10
Application #
2403148
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1986-09-01
Project End
1999-05-31
Budget Start
1997-06-01
Budget End
1999-05-31
Support Year
10
Fiscal Year
1997
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
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; Liu, J; Grayson, D R (2000) In utero exposure to serotonergic drugs alters neonatal expression of 5-HT(1A) receptor transcripts: a quantitative RT-PCR study. Int J Dev Neurosci 18:171-6
Moiseiwitsch, J R (2000) The role of serotonin and neurotransmitters during craniofacial development. Crit Rev Oral Biol Med 11:230-9
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
Lambert, H W; Lauder, J M (1999) Serotonin receptor agonists that increase cyclic AMP positively regulate IGF-I in mouse mandibular mesenchymal cells. Dev Neurosci 21:105-12
Moiseiwitsch, J R; Raymond, J R; Tamir, H et al. (1998) Regulation by serotonin of tooth-germ morphogenesis and gene expression in mouse mandibular explant cultures. Arch Oral Biol 43:789-800
Moiseiwitsch, J R; Lauder, J M (1997) Regulation of gene expression in cultured embryonic mouse mandibular mesenchyme by serotonin antagonists. Anat Embryol (Berl) 195:71-8
Buznikov, G A; Shmukler, Iu B; Lowder, J M (1997) [Changes in the physiological role of the neurotransmitters during individual development] Ross Fiziol Zh Im I M Sechenova 83:1-15
Moiseiwitsch, J R; Lauder, J M (1996) Stimulation of murine tooth development in organotypic culture by the neurotransmitter serotonin. Arch Oral Biol 41:161-5

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