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El gen supresor de tumores Brca1 es necesario para la proliferación celular embrionaria en el ratón
R Hakem1, J L de la Pompa, C Sirard
1Amgen Institute, Toronto, Ontario, Canada.
Cell
|June 28, 1996
Resumen
Las mutaciones en el gen BRCA1 están relacionadas con el cáncer. Los embriones de ratón mutante Homozygous Brca1 no se desarrollan adecuadamente y mueren temprano en la embriogénesis debido a la proliferación celular deteriorada.
Área de la Ciencia:
- Biología del desarrollo Biología del desarrollo.
- Genética La genética.
- Investigación de la investigación del cáncer.
Sus antecedentes:
- Las mutaciones en el gen BRCA1 están relacionadas con los cánceres hereditarios de mama y de ovario en los seres humanos.
- Los ratones Brca1+/- son viables y no desarrollan tumores a los 11 meses de edad.
Objetivo del estudio:
- Para investigar la letalidad embrionaria de las mutaciones homocigotas de Brca1.
- Comprender los mecanismos celulares subyacentes a los defectos del desarrollo embrionario en los mutantes de Brca1.
Principales métodos:
- Generación y análisis de ratones mutantes homocigotos Brca1(5-6).
- Estudios in vivo e in vitro del desarrollo embrionario, incluidos ensayos de proliferación celular y apoptosis.
- Análisis de la expresión génica, incluida la ciclina E, mdm-2 y p21.
Principales resultados:
- Los embriones mutantes homocigotos Brca1(5-6) exhiben fallas en el desarrollo antes del día 7.5 de la embriogénesis, con deterioro en la formación del mesodermo y desarrollo extraembrionario anormal.
- Los embriones mutantes muestran una reducción de la proliferación celular y una disminución de la expresión de ciclina E y mdm-2, junto con un aumento dramático en la expresión de p21.
- Los estudios in vitro confirmaron un deterioro grave del crecimiento del blastocisto en embriones mutantes.
Conclusiones:
- La letalidad embrionaria de los ratones mutantes Brca1 ((5-6) antes de la gastrulación es probablemente causada por una falla en el estallido proliferativo esencial para el desarrollo de la capa germinal.
- BRCA1 juega un papel crítico en la proliferación y desarrollo celular embrionario temprano, independiente de su papel en la reparación del ADN relacionado con la predisposición al cáncer.
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