Involvement of GABA in palate morphogenesis and its relation to diazepam teratogenesis in two mouse strains

Wee, Elizabeth L.; Zimmerman, Ernest F.

doi:10.1002/tera.1420280104

Cited by 63 publications

(20 citation statements)

References 19 publications

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“…This in vitro finding supports the hypothesis that impairment of any GABA function (in our patients, an excess) leads to cleft palate in vivo (51,52) and the involvement of GABRB3 in human CLP malformation (29). Treatment with RA markedly increased GABRB3 expression level in N-SP fibroblasts but had no effect on CLP-SP cells, implying that GABRB3 transcription was already at a maximum.…”

Section: R E S E a R C H A R T I C L E M O L M Esupporting

confidence: 90%

Retinoic Acid, GABA-ergic, and TGF-β Signaling Systems Are Involved in Human Cleft Palate Fibroblast Phenotype

Baroni

Bellucci

Lilli

et al. 2006

Mol Med

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During embryogenesis, a complex interplay between extracellular matrix (ECM) molecules, regulatory molecules, and growth factors mediates morphogenetic processes involved in palatogenesis. Transforming growth factor-β (TGF-β), retinoic acid (RA), and γ-aminobutyric acid (GABA)ergic signaling systems are also potentially involved. Using ]methionine incorporation, anion exchange chromatography, semiquantitative radioactive RT-PCR, and a TGF-β binding assay, we aimed to verify the presence of phenotypic differences between primary cultures of secondary palate (SP) fibroblasts from 2-year-old subjects with familial nonsyndromic cleft lip and/or palate (CLP-SP fibroblasts) and age-matched normal SP (N-SP) fibroblasts. The effects of RA-which, at pharmacologic doses, induces cleft palate in newborns of many species-were also studied. We found an altered ECM production in CLP-SP fibroblasts that synthesized and secreted more glycosaminoglycans (GAGs) and fibronectin (FN) compared with N-SP cells. In CLP-SP cells, TGF-β3 mRNA expression and TGF-β receptor number were higher and RA receptor-α (RARA) gene expression was increased. Moreover, we demonstrated for the first time that GABA receptor (GABRB3) mRNA expression was upregulated in human CLP-SP fibroblasts. In N-SP and CLP-SP fibroblasts, RA decreased GAG and FN secretion and increased TGF-β3 mRNA expression but reduced the number of TGF-β receptors. TGF-β receptor type I mRNA expression was decreased, TGF-β receptor type II was increased, and TGF-β receptor type III was not affected. RA treatment increased RARA gene expression in both cell populations but upregulated GABRB3 mRNA expression only in N-SP cells. These results show that CLP-SP fibroblasts compared with N-SP fibroblasts exhibit an abnormal phenotype in vitro and respond differently to RA treatment, and suggest that altered crosstalk between RA, GABAergic, and TGF-β signaling systems could be involved in human cleft palate fibroblast phenotype.

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Section: R E S E a R C H A R T I C L E M O L M Esupporting

confidence: 90%

Retinoic Acid, GABA-ergic, and TGF-β Signaling Systems Are Involved in Human Cleft Palate Fibroblast Phenotype

Baroni

Bellucci

Lilli

et al. 2006

Mol Med

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“…Administration of the GABA potentiator diazepam to pregnant mice induces cleft palate in their offspring (24). GABA application to E14.5 mouse embryos in short-term culture also inhibits palate development (25). Furthermore, cleft palate and neurological disorders are observed in pinkeyed cleft palate (p) mutant mice, which are thought to be defective in the ␤3 subunit of GABA A receptor (26,27).…”

Section: Resultsmentioning

confidence: 99%

Cleft palate and decreased brain γ-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase

Asada

Kawamura²,

Maruyama³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

522

451

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In addition to its role as an inhibitory neurotransmitter, ␥-aminobutyric acid (GABA) is presumed to be involved in the development and plasticity of the nervous system. GABA is synthesized by glutamic acid decarboxylase (GAD), but the respective roles of its two isoforms (GAD65 and 67) have not been determined. The selective elimination of each GAD isoform by gene targeting is expected to clarify these issues. Recently we have produced GAD65 ؊͞؊ mice and demonstrated that lack of GAD65 does not change brain GABA contents or animal behavior, except for a slight increase in susceptibility to seizures. Here we report the production of GAD67 ؊͞؊ mice. These mice were born at the expected frequency but died of severe cleft palate during the first morning after birth. GAD activities and GABA contents were reduced to 20% and 7%, respectively, in the cerebral cortex of the newborn GAD67 ؊͞؊ mice. Their brain, however, did not show any discernible defects. Previous pharmacological and genetic investigations have suggested the involvement of GABA in palate formation, but this is the first demonstration of a role for GAD67-derived GABA in the development of nonneural tissue.

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“…Cell culture studies have demonstrated that GABA can promote the survival, differentiation, and migration of embryonic neurons (2,4,8). In addition, both genetic and teratological studies have shown that GABA signaling may be involved in normal craniofacial development (9)(10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

“…Previous observations have suggested a role for GABA in palate development. Some of these earlier studies showed that drugs potentiating GABA action can induce cleft palate during a critical period of mouse palate development (12)(13)(14). However, these studies used high drug doses to produce the cleft palate phenotype, suggesting that the effect might be nonspecific.…”

mentioning

confidence: 99%

Cleft palate in mice with a targeted mutation in the γ-aminobutyric acid-producing enzyme glutamic acid decarboxylase 67

Condie

Bain

Gottlieb

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

135

103

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The functions of neurotransmitters in fetal development are poorly understood. Genetic observations have suggested a role for the inhibitory amino acid neurotransmitter ␥-aminobutyric acid (GABA) in the normal development of the mouse palate. Mice homozygous for mutations in the ␤-3 GABA A receptor subunit develop a cleft secondary palate. GABA, the ligand for this receptor, is synthesized by the enzyme glutamic acid decarboxylase. We have disrupted one of the two mouse Gad genes by gene targeting and also find defects in the formation of the palate. The striking similarity in phenotype between the receptor and ligand mutations clearly demonstrates a role for GABA signaling in normal palate development.

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Involvement of GABA in palate morphogenesis and its relation to diazepam teratogenesis in two mouse strains

Cited by 63 publications

References 19 publications

Retinoic Acid, GABA-ergic, and TGF-β Signaling Systems Are Involved in Human Cleft Palate Fibroblast Phenotype

Retinoic Acid, GABA-ergic, and TGF-β Signaling Systems Are Involved in Human Cleft Palate Fibroblast Phenotype

Cleft palate and decreased brain γ-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase

Cleft palate in mice with a targeted mutation in the γ-aminobutyric acid-producing enzyme glutamic acid decarboxylase 67

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