Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development

Thomas, Kirk R.; Capecchi, Mario R.

doi:10.1038/346847a0

Cited by 897Developmental Biology and Gene RegulationNeurogenesis and neuroplasticity mechanismsWnt/β-catenin signaling in development and cancer

Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development

Thomas, Kirk R., Capecchi, Mario R.·1990·Nature

DOI 10.1038/346847a0

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Abstract

The int-1 proto-oncogene was first identified as a gene activated in virally induced mouse mammary tumours. Expression studies, however, suggest that the normal function of this gene may be in spermatogenesis and in the development of the central nervous system. Genes sharing sequence similarity with int-1 have been found throughout the animal kingdom. For example, int-1 has 54% amino-acid identity to the Drosophila segment polarity gene wingless (wg). Both the int-1 and wg gene products seem to be secreted proteins, presumably involved in cell-cell signalling. We have now explored the function of int-1 in the mouse by disrupting one of the two int-1 alleles in mouse embryo-derived stem cells using positive-negative selection. This cell line was used to generate a chimaeric mouse that transmitted the mutant allele to its progeny. Mice heterozygous for the int-1 null mutation are normal and fertile, whereas mice homozygous for the mutation may exhibit a range of phenotypes from death before birth to survival with severe ataxia. The latter pathology in mice and humans is often associated with defects in the cerebellum. Examination of int-1-/int-1- mice at several stages of embryogenesis revealed severe abnormalities in the development of the mesencephalon and metencephalon indicating a prominent role for the int-1 protein is in the induction of the mesencephalon and cerebellum.

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Authors: Thomas, K. R., & Capecchi, M. R.
Affiliations: Howard Hughes Medical Institute (US)
ORCID: Capecchi, Mario R.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1990-08
Volume: 346
Issue: 6287
Pages: 847-850
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/346847a0
OpenAlex: W2033291406
Cited by: 896
References: 30
Citations by year: 2026: 3 · 2025: 8 · 2024: 8 · 2023: 14 · 2022: 10 · 2021: 13 · 2020: 19 · 2019: 9 · 2018: 6 · 2017: 18 · 2016: 20 · 2015: 20 · 2014: 12 · 2013: 35 · 2012: 26
FWCI: 23.82
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords: cerebellar development, midbrain development, metencephalon, ataxia, cell-to-cell communication, chimeric mice, embryonic stem cells, spermatogenesis
MeSH terms: Proto-Oncogene Mas, Animals, Blastocyst, Cell Line, Cerebellum, Chimera, DNA, Female, Genotype, Heterozygote, Homozygote, Male, Mesencephalon, Mice, Inbred C57BL, Motor Activity, Mutation, Nucleic Acid Hybridization, Proto-Oncogene Proteins, Stem Cells, Transfection, Zebrafish Proteins, Wnt Proteins, Wnt1 Protein, Mice

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Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development

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