Evidence from a variety of animal species suggests that neurotransmitters play roles in morphogenesis prior to development of neurotransmission. For example, studies in the chick embryo demonstrate sites of uptake and/or synthesis for serotonin (5-HT) and norepinephrine (NE) in the early neural tube and notochord, and drugs which interfere with the uptake, synthesis or metabolism of these substances produce malformations of the nervous system. In the mouse, such drugs cause similar malformations, but no studies have yet been conducted to determine whether 5-HT or NE sites exist in this or other mammalian species, which could provide a good model for studies of drug-induced malformations in the human. In preliminary studies, using whole embryo culture of mouse embryos, we have identified sites of 5-HT uptake and/or synthesis by incubation of embryos with 5-HT or precursors followed by immunocytochemical staining of fixed sections with an antiserum to 5-HT. Using this approach, we have localized 5-HT uptake sites in the developing heart, head ectoderm, epiphysis, mandibular and pharyngeal arches, palate, otocyst (ear), and hindgut underlying the caudal neural tube during closure. Using the whole embryo culture system, we propose to study these 5-HT sites in terms of 1) their developmental timecourse and pharmacologic characterization, and 2) as potential foci for teratogenic effects of 5-HT-interactive drugs. The possible morphogenetic roles of other neurotransmitters for which we have antisera (e.g., catecholamines and GABA) will also be examined using the same in vitro approach in which we will first explore sites of uptake and/or synthesis and then test appropriate drugs for related teratogenic effects. These studies should produce new information regarding roles for neurotransmitters in morphogenesis as well as providing valuable insights into possible site-specific malformations caused by psychoactive drugs taken by the pregnant woman.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD022052-03
Application #
3321317
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1986-09-01
Project End
1990-03-31
Budget Start
1988-09-01
Budget End
1990-03-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
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
Buznikov, G A; Shmukler, Y B; Lauder, J M (1996) From oocyte to neuron: do neurotransmitters function in the same way throughout development? Cell Mol Neurobiol 16:537-59

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