Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene

doi:10.1016/0092-8674(91)90011-M

Cell

Volume 65, Issue 7, 28 June 1991, Pages 1153-1163

https://doi.org/10.1016/0092-8674(91)90011-M Get rights and content

Abstract

The c-abl proto-oncogene, which encodes a cytoplasmic protein-tyrosine kinase, is expressed throughout murine gestation and ubiquitously in adult mouse tissues. However, its levels are highest in thymus, spleen, and testes. To examine the in vivo role of c-abl, the gene was disrupted in embryonic stem cells, and the resulting genetically modified cells were used to establish a mouse strain carrying the mutation. Most mice homozygous for the c-abl mutation became runted and died 1 to 2 weeks after birth. In addition, many showed thymic and splenic atrophy and a T and B cell lymphopenia.

References (39)

C.N. Adra et al.
Cloning and expression of the mouse pgk-1 gene and the nucleotide sequence of its promoter
Gene
(1987)
Y. Ben-Neriah et al.
Alternative 5′ exons in c-abl mRNA
Cell
(1986)
T. Elkins et al.
Genetic analysis of a Drosophila neural cell adhesion molecule: interaction of fasciclin I and Abelson tyrosine kinase mutations
Cell
(1990)
F.B. Gertler et al.
Drosophila abl tyrosine kinase in embryonic CNS axons: a role in axonogenesis is revealed through dosage-sensitive interactions with disabled
Cell
(1989)
M.J. Henkemeyer et al.
The Drosophila Abelson proto-oncogene homolog: identification of mutant alleles that have pleiotropic effects late in development
Cell
(1987)
M.J. Henkemeyer et al.
A novel tyrosine kinase-independent function of Drosophila abl correlates with proper subcellular localization
Cell
(1990)
K. Ikuta et al.
A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells
Cell
(1990)
E. Shtivelman et al.
Alternative splicing of RNAs transcribed from the human abl gene and from the bcr-abl fused gene
Cell
(1986)
E.M. Southern
Detection of specific sequences among DNA fragments separated by gel electrophoresis
J. Mol. Biol.
(1975)
K.R. Thomas et al.
Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells
Cell
(1987)

R.A. Van Etten et al.

The mouse type IV c-abl gene product is a nuclear protein, and activation of transforming ability is associated with cytoplasmic localization

Cell

(1989)

A. ar-Rushdi et al.

Fusion of the bcr and the c-abl genes in Ph′-positive acute lymphocytic leukemia with no rearrangement in the breakpoint cluster region

Oncogene

(1988)

C.R. Bartram et al.

c-abl and bcr are rearranged in a Ph¹-negative CML patient

EMBO J.

(1985)

A. Bernards et al.

Four murine c-abl mRNAs arise by usage of two transcriptional promoters and alternative splicing

Oncogene

(1988)

A. Bradley

Production and analysis of chimaeric mice

S.S. Clark et al.

Unique forms of the abl tyrosine kinase distinguish Ph¹-positive CML from Ph¹-positive ALL

Science

(1987)

G. Grosveld et al.

The chronic myelocytic cell line K562 contains a breakpoint in bcr and produces a chimeric bcrlc-abl transcript

Mol. Cell. Biol.

(1986)

S.K. Hanks et al.

The protein kinase family: conserved features and deduced phylogeny of the catalytic domains

Science

(1988)

N. Heisterkamp et al.

Acute leukaemia in bcrlabl transgenic mice

Nature

(1990)

Cited by (1201)

c-Abl kinase-mediated phosphorylation of γ-tubulin promotes γ-tubulin ring complexes assembly and microtubule nucleation
2022, Journal of Biological Chemistry
Cytoskeletal microtubules (MTs) are nucleated from γ-tubulin ring complexes (γTuRCs) located at MT organizing centers (MTOCs), such as the centrosome. However, the exact regulatory mechanism of γTuRC assembly is not fully understood. Here, we showed that the nonreceptor tyrosine kinase c-Abl was associated with and phosphorylated γ-tubulin, the essential component of the γTuRC, mainly on the Y443 residue by in vivo (immunofluorescence and immunoprecipitation) or in vitro (surface plasmon resonance) detection. We further demonstrated that phosphorylation deficiency significantly impaired γTuRC assembly, centrosome construction, and MT nucleation. c-Abl/Arg deletion and γ-tubulin Y443F mutation resulted in an abnormal morphology and compromised spindle function during mitosis, eventually causing uneven chromosome segregation. Our findings reveal that γTuRC assembly and nucleation function are regulated by Abl kinase-mediated γ-tubulin phosphorylation, revealing a fundamental mechanism that contributes to the maintenance of MT function.
c-Abl regulates a synaptic plasticity-related transcriptional program involved in memory and learning
2021, Progress in Neurobiology
Memory consolidation requires activation of a gene expression program that allows de novo protein synthesis. But the molecular mechanisms that favour or restrict that program are poorly understood. The kinase c-Abl can modulate gene expression through transcription factors and chromatin modifiers. Here, we show that c-Abl ablation in the brain improves learning acquisition and memory consolidation in mice. Its absence also affects gene expression profiles in the mouse hippocampus. We found that genes involved in synaptic plasticity and actin cytoskeleton dynamics, such as Arp2 and Thorase, are up-regulated at the mRNA and protein levels in trained c-Abl KO mice and by a chemical-LTP stimulus. Trained c-Abl KO mice also show that dendritic spines are larger than in wild-type mice and present at a higher density. These results indicate that c-Abl kinase is an important part of the mechanism that limits or restricts signalling of relevant gene programs involved in morphological and functional spine changes upon neuronal stimulation.
Determination of c-Abl tyrosine kinase and mTERT catalytic subunit of telomerase expression level during prenatal-postnatal mouse ovary-testis development
2020, Reproductive Biology
Expression levels of genes involved in the development of germ cells vary throughout the process from bipotential gonadal period to adult gonadal formation. In mice, developments of female and male reproductive system are regulated by germ cell-specific factors and hormones, and determinative days in this regulation are very important. c-Abl is a non-receptor tyrosine kinase with cellular functions including cell proliferation, growth and development. mTERT is involved in maintaining telomerase activity and proliferation of surviving cells. We suggested that c-Abl and mTERT might be important for the healthy development of prenatal and postnatal mouse ovary and testis. We aim to demonstrate localization and expressions of c-Abl and mTERT in crucial days of ovary and testis development in prenatal and postnatal period in mouse by immunofluorescence staining and qRT-PCR, respectively. The importance of c-Abl and mTERT expressions during the healthy gonadal development is indicated in the prenatal and postnatal gonadal development. Also, protein expression levels were detected by Western Blot in only postnatal ovary and testis. Determining the functions of the c-Abl and mTERT throughout the process will be important in terms of understanding the infertility cases in the female and male with future studies.
Imatinib mesylate effects on zebrafish reproductive success: Gonadal development, gamete quality, fertility, embryo-larvae viability and development, and related genes
2019, Toxicology and Applied Pharmacology
Imatinib (IM) is a tyrosine kinase (TK) inhibitor (TKI) used to treat chronic myeloid leukemia. Clinical case reports and a few laboratory mammal studies provide inconclusive evidence about its deleterious effects on reproduction. The aim of the current study was to evaluate the potential of zebrafish to characterize IM-induced effects on reproduction and clarify IM effects on reproductive success. To this end, we exposed adult zebrafish to four concentrations of IM for 30 days followed by a 30-day depuration period. IM exposure caused a concentration-dependent, irreversible, suppression of folliculogenesis, reversible decrease in sperm density and motility, decreased fecundity and fertility, but no significant change in atretic follicle abundance. We also observed IM-induced premature hatching, but no significant change in embryo-larvae survivability. However, we found significant IM-induced morphometric malformations. IM decreased expression of vegfaa and igf2a (two reproductive-, angiogenic-, and growth-related genes) in testes and ovaries. The results demonstrate IM can induce significant changes in critical reproductive endpoints and zebrafish as a suitable model organism to show effects of IM on reproduction. The findings suggest that TKI effects on reproductive success should be considered.
Grb7, Grb10 and Grb14, encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism
2024, bioRxiv
ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias
2023, Blood Cancer Journal

View all citing articles on Scopus

^†: Present address: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, England.

View full text

Cell

ArticleNeonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene

Abstract

Gene

Cell

Cell

Cell

Cell

Cell

Cell

Cell

J. Mol. Biol.

Cell

Cell

Fusion of the bcr and the c-abl genes in Ph′-positive acute lymphocytic leukemia with no rearrangement in the breakpoint cluster region

Oncogene

c-abl and bcr are rearranged in a Ph1-negative CML patient

EMBO J.

Four murine c-abl mRNAs arise by usage of two transcriptional promoters and alternative splicing

Oncogene

Production and analysis of chimaeric mice

Unique forms of the abl tyrosine kinase distinguish Ph1-positive CML from Ph1-positive ALL

Science

The chronic myelocytic cell line K562 contains a breakpoint in bcr and produces a chimeric bcrlc-abl transcript

Mol. Cell. Biol.

The protein kinase family: conserved features and deduced phylogeny of the catalytic domains

Science

Acute leukaemia in bcrlabl transgenic mice

Nature

Article
Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene

c-abl and bcr are rearranged in a Ph¹-negative CML patient

Unique forms of the abl tyrosine kinase distinguish Ph¹-positive CML from Ph¹-positive ALL