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Cardiovascular and craniofacial defects in Crk-null mice
Tae-Ju Park1, Kelli Boyd, Tom Curran
1St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Abstract:
The Crk adaptor protein, which is encoded by two splice variants termed CrkI and CrkII, contains both SH2 and SH3 domains but no catalytic region. It is thought to function in signal transduction processes involved in growth regulation, cell transformation, cell migration, and cell adhesion. Although the function of Crk has been studied in considerable detail in cell culture, its biological role in vivo is still unclear, and no Crk-knockout mouse model has been available. Therefore, we generated a complete null allele of Crk in mice by using the Cre-loxP recombination approach. The majority of Crk-null mice die at late stages of embryonic development, and the remainder succumb shortly after birth. Embryos lacking both CrkI and CrkII exhibited edema, hemorrhage, and cardiac defects. Immunohistochemical examination suggested that defects in vascular smooth muscle caused dilation and rupturing of blood vessels. Problems in nasal development and cleft palate were also observed. These data indicate that Crk is involved in cardiac and craniofacial development and that it plays an essential role in maintaining vascular integrity during embryonic development.
Insights
Crk adaptor proteins are essential for embryonic development, crucial for cardiac and craniofacial formation and maintaining vascular integrity. Crk-null mice exhibit severe developmental defects, leading to embryonic lethality.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Crk adaptor proteins (CrkI and CrkII) possess SH2 and SH3 domains, implicated in growth regulation, cell transformation, migration, and adhesion.
- In vivo functions of Crk remain largely unelucidated due to the absence of a Crk-knockout mouse model.
Purpose of the Study:
- To investigate the in vivo biological role of Crk adaptor proteins.
- To generate and characterize a Crk-null mouse model to study its developmental functions.
Main Methods:
- Utilized the Cre-loxP recombination system to generate a complete null allele for Crk in mice.
- Conducted phenotypic analysis of Crk-null embryos, including morphological and immunohistochemical examinations.
Main Results:
- Crk-null mice exhibited high embryonic lethality, with death occurring during late embryonic development or shortly after birth.
- Embryos lacking Crk displayed significant edema, hemorrhage, cardiac defects, and craniofacial abnormalities such as cleft palate.
- Immunohistochemistry revealed vascular smooth muscle defects, leading to blood vessel dilation and rupture, indicating compromised vascular integrity.
Conclusions:
- Crk adaptor proteins are indispensable for embryonic development, particularly in cardiac and craniofacial morphogenesis.
- Crk plays a critical role in maintaining vascular integrity during embryonic development, and its absence leads to severe vascular defects and lethality.
