Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator...

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• The transcriptional coactivator p300 and its family member CBP regulate numerous signal-dependent gene expression events.
• Histone acetyltransferase (HAT) activity is a key feature of p300 and CBP function.

Purpose of the Study:

• To investigate the essential role of p300 in mammalian development by generating and analyzing mice lacking a functional p300 gene.
• To determine the impact of p300 deficiency on embryonic development, cell proliferation, and transcriptional regulation.

Main Methods:

• Generation of genetically modified mice with a non-functional p300 gene (p300 knockout).
• Analysis of embryonic lethality and developmental defects in p300 nullizygous and heterozygous embryos.
• Characterization of cellular and transcriptional defects in cells derived from p300-deficient embryos.

Main Results:

• Mice lacking functional p300 (p300 nullizygous) exhibited embryonic lethality between days 9 and 11.5 of gestation.
• Developmental defects observed included impaired neurulation, reduced cell proliferation, and cardiac abnormalities.
• p300-deficient embryonic cells showed specific transcriptional defects and poor proliferation.
• Surprisingly, p300 heterozygotes also displayed significant embryonic lethality.
• Double heterozygosity for p300 and CBP invariably resulted in embryonic death, indicating gene dosage sensitivity.

Conclusions:

• Mouse embryonic development is highly sensitive to the dosage of p300 and CBP.
• Genetic evidence confirms that p300, a coactivator with histone acetyltransferase activity, is indispensable for mammalian cell proliferation and overall development.
• These findings underscore the critical importance of p300 in fundamental biological processes.