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

October 14, 1997
94 (21) 11451-11455

Abstract

The functions of neurotransmitters in fetal development are poorly understood. Genetic observations have suggested a role for the inhibitory amino acid neurotransmitter γ-aminobutyric acid (GABA) in the normal development of the mouse palate. Mice homozygous for mutations in the β-3 GABAA 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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Acknowledgments

We thank C. Lenz, M. Allen, G. Peterson, E. Nakashima, M. Wagstaff, and S. Barnett for excellent technical assistance and L. Oswald for preparation of the manuscript.

References

1
S L Erdo, J R Wolff J Neurochem 54, 363–372 (1990).
2
G Barbin, H Pollard, J L Gaiarsa, Y Ben-Ari Neurosci Lett 152, 150–154 (1993).
3
J L LoTurco, D F Owens, M J S Heath, M B E Davis, A R Kriegstein Neuron 15, 1287–1298 (1995).
4
T N Behar, L Yong-Xin, H T Tran, W Ma, V Dunlap, C Scott, J L Barker J Neurosci 16, 1808–1818 (1996).
5
P Rorsman, P O Berggren, K Bokvist, H Ericson, H Mohler, C G Ostnson, P A Smith Nature (London) 341, 233–236 (1989).
6
A Reetz, M Solimena, M Matteoli, F Folli, K Takei, P De Camilli EMBO J 10, 1275–1284 (1991).
7
S Baekkeskov, H-J Aanstoot, S Christgau, A Reetz, M Solimena, M Cascalho, F Folli, H Richter-Oleson, P DeCamilli Nature (London) 347, 151–156 (1990).
8
J Liu, A L Morrow, L Devaud, D R Grayson, J M Lauder J Neurosci 17, 2420–2428 (1997).
9
C T Culiat, L Stubbs, R D Nicholls, C S Montgomery, L B Russell, D K Johnson, E M Rinchik Proc Natl Acad Sci USA 90, 5105–5109 (1993).
10
C T Culiat, L J Stubbs, R P Woychik, L B Russell, D K Johnson, E M Rinchik Nat Genet 11, 344–346 (1995).
11
G E Homanics, T M DeLorey, L L Firestone, J J Quinlan, A Handforth, N L Harrison, M D Krasowski, C E M Rick, E R Korpi, R Makela, M H Brilliant, N Hagiwara, C Ferguson, K Snyder, R W Olsen Proc Natl Acad Sci USA 94, 4143–4148 (1997).
12
E F Zimmerman, E L Wee Curr Top Dev Biol 19, 37–63 (1984).
13
R P Miller, B A Becker Toxicol Appl Pharmacol 32, 53–61 (1975).
14
E L Wee, E F Zimmerman Teratology 28, 15–22 (1983).
15
J R Cooper, F E Bloom, R H Roth The Biochemical Basis of Neuropharmacology (Oxford Univ. Press, Oxford, U.K., 1996).
16
M G Erlander, N J K Tillakaratne, S Feldblum, N Patel, A J Tobin Neuron 7, 91–100 (1991).
17
K R Thomas, M R Capecchi Cell 51, 503–512 (1987).
18
Z Katarova, G Szabo, E Mugnaini, R J Greenspan Eur J Neurosci 2, 190–202 (1990).
19
A Nagy, J Rossant, R Nagy, W Abramow-Newerly, J C Roder Proc Natl Acad Sci USA 90, 8424–8428 (1993).
20
B G Condie, M R Capecchi Development (Cambridge, UK) 119, 579–595 (1993).
21
G Bain, T P Ramkumar, J M Cheng, D I Gottlieb Mol Brain Res 17, 23–30 (1993).
22
M Qiu, A Bulfone, S Martinez, J J Meneses, K Shimamura, R A Pederson, J L R Rubenstein Genes Dev 9, 2523–2538 (1995).
23
I Saxen, L Saxen Lancet ii, 498 (1975).
24
D Aarskog Lancet ii, 921 (1975).
25
M J Safra, G P Oakley Lancet ii, 478–480 (1975).
26
L Rosenberg, A A Mitchell, J L Parsells, H Pashayan, C Louik, S Shapiro N Engl J Med 309, 1282–1285 (1983).
27
G Moore, A Ivens, J Chambers, A Bjornsson, A Arnason, O Jensson, R Williamson Development (Cambridge, UK) Suppl 103, 233–239 (1988).
28
D M Juriloff, M J Harris J Hered 82, 402–405 (1991).

Information & Authors

Information

Published in

The cover image for PNAS Vol.94; No.21
Proceedings of the National Academy of Sciences
Vol. 94 | No. 21
October 14, 1997
PubMed: 9326630

Classifications

Submission history

Accepted: August 14, 1997
Published online: October 14, 1997
Published in issue: October 14, 1997

Acknowledgments

We thank C. Lenz, M. Allen, G. Peterson, E. Nakashima, M. Wagstaff, and S. Barnett for excellent technical assistance and L. Oswald for preparation of the manuscript.

Authors

Affiliations

Brian G. Condie
Howard Hughes Medical Institute, Department of Human Genetics, University of Utah, School of Medicine, Salt Lake City, UT 84112; and Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110-1093
Gerard Bain
Howard Hughes Medical Institute, Department of Human Genetics, University of Utah, School of Medicine, Salt Lake City, UT 84112; and Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110-1093
David I. Gottlieb
Howard Hughes Medical Institute, Department of Human Genetics, University of Utah, School of Medicine, Salt Lake City, UT 84112; and Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110-1093
Mario R. Capecchi
Howard Hughes Medical Institute, Department of Human Genetics, University of Utah, School of Medicine, Salt Lake City, UT 84112; and Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110-1093

Notes

Present address: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912.
Present address: Department of Medical Biochemistry, University of Calgary, Calgary, AB, Canada T2N 4N1.
To whom reprint requests should be addressed at: Howard Hughes Medical Institute, University of Utah, 15 North 2030 East Street, Suite 5400, Salt Lake City, UT 84112-5331. e-mail: [email protected].
Contributed by Mario R. Capecchi

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    Cleft palate in mice with a targeted mutation in the γ-aminobutyric acid-producing enzyme glutamic acid decarboxylase 67
    Proceedings of the National Academy of Sciences
    • Vol. 94
    • No. 21
    • pp. 11109-11746

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