DOI: 10.1101/gad.8.9.1019. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.

Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.

10.1101/gad.8.9.1019

Crossref journal-article

Cold Spring Harbor Laboratory

Genes & Development (246)

Abstract

The neurofibromatosis (NF1) gene shows significant homology to mammalian GAP and is an important regulator of the ras signal transduction pathway. To study the function of NF1 in normal development and to try and develop a mouse model of NF1 disease, we have used gene targeting in ES cells to generate mice carrying a null mutation at the mouse Nf1 locus. Although heterozygous mutant mice, aged up to 10 months, likely attributable to a severe malformation of the heart. Interestingly, mutant embryos also display hyperplasia of neural crest-derived sympathetic ganglia. These results identify new roles for NF1 in development and indicate that some of the abnormal growth phenomena observed in NF1 patients can be recapitulated in neurofibromin-deficient mice.

Bibliography

Brannan, C. I., Perkins, A. S., Vogel, K. S., Ratner, N., Nordlund, M. L., Reid, S. W., Buchberg, A. M., Jenkins, N. A., Parada, L. F., & Copeland, N. G. (1994). Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes & Development, 8(9), 1019â1029.

Authors 10

C I Brannan (first)
A S Perkins (additional)
K S Vogel (additional)
N Ratner (additional)
M L Nordlund (additional)
S W Reid (additional)
A M Buchberg (additional)
N A Jenkins (additional)
L F Parada (additional)
N G Copeland (additional)

References 44 Referenced 535

{'key': '2021111418143997000_8.9.1019.1', 'first-page': '56', 'article-title': 'Neurofibromatosis and cancer.', 'volume': '486', 'year': '1986', 'journal-title': 'Ann. N.Y. Acad. Sci.'} / Ann. N.Y. Acad. Sci. / Neurofibromatosis and cancer. (1986)
10.1016/0092-8674(90)90151-4
10.1016/0092-8674(85)90280-6
10.1038/356713a0
10.1093/hmg/2.6.645
Bradley, A. 1987. Production and analysis of chimeric mice. IRL Press, Oxford, England.
10.1038/347291a0
10.1016/0092-8674(95)90307-0
10.1073/pnas.75.6.2986
10.1002/aja.1001950307 / Dev. Dynamics / Neurofibromin, a predominantly neuronal GTPase activating protein in the adult, is ubiquitously expressed during development. (1992)
10.1016/0896-6273(92)90270-N
10.1016/0092-8674(92)90407-4
{'key': '2021111418143997000_8.9.1019.13', 'first-page': '2151', 'article-title': 'Catalytic properties, tissue and intracellular distribution of neurofibromin.', 'volume': '7', 'year': '1992', 'journal-title': 'Oncogene'} / Oncogene / Catalytic properties, tissue and intracellular distribution of neurofibromin. (1992)
10.1016/0896-6273(93)90324-K
10.1093/hmg/2.7.989
10.1016/0092-8674(90)90054-I
Hogan, B., F. Constantini, and E. Lacy. 1986. Manipulating the mouse embryo: A laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
10.1006/dbio.1994.1052
10.1128/jvi.43.1.26-36.1982 / J. Virol. / Organization, distribution, and stability of endogenous ecotropic murine leukemia virus DNA sequences in chromosomes of Mus musculus. (1982)
10.1073/pnas.90.12.5539
{'key': '2021111418143997000_8.9.1019.21', 'first-page': '92', 'volume': '8', 'year': '1972', 'journal-title': 'Birth defects: Original article series'} / Birth defects: Original article series (1972)
10.1126/science.6844926
10.1073/pnas.68.4.820
10.1093/nar/19.15.4293
10.1038/ng0293-122
Luna, L.G. 1968. Manual of histologic staining methods of the Armed Forces Institute of Pathology, pp. 195â196. McGraw-Hill, New York.
10.1016/0888-7543(91)90017-9
10.1016/0092-8674(91)90641-B
10.1016/0092-8674(90)90150-D
{'key': '2021111418143997000_8.9.1019.30', 'first-page': '1555', 'article-title': 'Differential expression of two types of the neurofibromatosis type 1 (NF1) gene transcripts related to neuronal differentiation.', 'volume': '6', 'year': '1991', 'journal-title': 'Oncogene'} / Oncogene / Differential expression of two types of the neurofibromatosis type 1 (NF1) gene transcripts related to neuronal differentiation. (1991)
10.1038/318073a0
10.1523/JNEUROSCI.13-04-01588.1993 / J. Neurosci. / Neurofibromin is enriched in the endoplasm reticulum of CNS neurons. (1993)
10.1056/NEJM198112313052704 / N. Engl. J. Med. / Von Recklinghausen neurofibromatosis. (1981)
10.1056/NEJM199105023241812 / N. Engl. J. Med. / Neurofibromatosis: Past, present and future. (1991)
Riccardi, V.M. and J.E. Eichner. 1986. Neurofibromatosis: Phenotype, natural history and pathogenesis. Johns Hopkins University Press, Baltimore, MD.
10.1038/323445a0
10.1093/genetics/117.1.85 / Genetics / Allelic variation within the Emv-15 locus defines genomic sequences closely linked to the agouti locus on mouse chromosome 2. (1987)
10.1038/ng0193-62
10.1016/0092-8674(87)90646-5
10.1016/0092-8674(90)90252-A
10.1126/science.2134734
10.1007/BF01258147
10.1016/0092-8674(90)90149-9
10.1016/0092-8674(90)90024-9

Dates

Type	When
Created	18 years, 2 months ago (June 5, 2007, 5:15 p.m.)
Deposited	3 years, 9 months ago (Nov. 14, 2021, 9:19 p.m.)
Indexed	1 hour, 18 minutes ago (Sept. 3, 2025, 2:20 a.m.)
Issued	31 years, 4 months ago (May 1, 1994)
Published	31 years, 4 months ago (May 1, 1994)
Published Online	31 years, 4 months ago (May 1, 1994)
Published Print	31 years, 4 months ago (May 1, 1994)

Funders 0

None

BibTeX

@article{Brannan_1994, title={Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.}, volume={8}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.8.9.1019}, DOI={10.1101/gad.8.9.1019}, number={9}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Brannan, C I and Perkins, A S and Vogel, K S and Ratner, N and Nordlund, M L and Reid, S W and Buchberg, A M and Jenkins, N A and Parada, L F and Copeland, N G}, year={1994}, month=may, pages={1019–1029} }

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