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Updated: Jun 22, 2026
Inducible and Reversible Dominant-negative (DN) Protein Inhibition
Published on: January 7, 2019
Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice
P Soriano1, C Montgomery, R Geske
1Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030.
Abstract:
To understand the normal, physiological role of the c-src proto-oncogene, a null mutation was introduced into the gene by homologous recombination in mouse embryonic stem cells. Two independent targeted clones were used to generate chimeras that transmitted the mutated allele to their offspring. Intercrossing of heterozygotes gave rise to live born homozygotes, but most of these mice died within the first few weeks of birth. Histological and hematological examination of the homozygous mutants did not reveal detectable abnormalities in the brain or platelets, where src is most highly expressed. However, these mutants were deficient in bone remodeling, indicating impaired osteoclast function, and developed osteopetrosis. These results demonstrate that src is not required for general cell viability (possibly because of functional overlap with other tyrosine kinases related to src) and uncover an essential role for src in bone formation.
Insights
The c-src proto-oncogene is essential for normal bone remodeling and osteoclast function. Mice lacking c-src exhibit impaired bone formation and osteopetrosis, demonstrating its critical role in skeletal development.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- The c-src proto-oncogene is a non-receptor tyrosine kinase implicated in various cellular processes.
- Its precise physiological role, particularly in normal development and tissue homeostasis, remains incompletely understood.
Purpose of the Study:
- To elucidate the normal physiological function of the c-src proto-oncogene.
- To investigate the consequences of a null mutation in the c-src gene on mouse development and physiology.
Main Methods:
- Generation of c-src null mutant mice using homologous recombination in embryonic stem cells.
- Analysis of homozygous mutant mice through histological and hematological examinations.
- Assessment of bone remodeling and osteoclast function in mutant mice.
Main Results:
- Homozygous c-src mutant mice exhibit impaired bone remodeling and develop osteopetrosis.
- Osteoclast function is significantly impaired in the absence of c-src.
- No detectable abnormalities were observed in the brain or platelets, despite high c-src expression in these tissues.
Conclusions:
- The c-src proto-oncogene is not essential for general cell viability, likely due to functional redundancy with related tyrosine kinases.
- c-src plays a critical and essential role in bone formation and osteoclast-mediated bone remodeling.
- Targeting c-src may offer therapeutic potential for bone-related disorders.
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