Extensive brain hemorrhage and embryonic lethality in a mouse null mutant of CREB-binding protein.
CREB-binding protein (CBP) is a transcriptional co-activator which is required by many transcription factors. Rubinstein-Taybi syndrome (RTS), which is an autosomal dominant syndrome characterized by abnormal pattern formation, is associated with mutations in the human CBP gene. Various abnormalities occur at high frequency in the skeletal system of heterozygous Cbp-deficient mice, but some features of RTS such as cardiac anomalies do not, suggesting that some symptoms of RTS are caused by a dominant-negative mechanism. Here we report the characterization of homozygous Cbp-deficient mice. Homozygous mutants died around E10.5-E12.5, apparently as a result of massive hemorrhage caused by defective blood vessel formation in the central nervous system, and exhibited apparent developmental retardation as well as delays in both primitive and definitive hematopoiesis. Cbp-deficient embryos exhibited defective neural tube closure which was similar to those observed in twist-deficient embryos. However, a decrease in the level of twist expression was not observed in Cbp-deficient embryos. Anomalous heart formation, a feature of RTS patients and mice mutated in the CBP-related molecule, p300, was not observed in Cbp-deficient embryos. Since both Cbp and p300 are ubiquitously expressed in embryonic tissues including the developing heart, these results suggest that cardiac anomalies observed in RTS patients may be caused by a dominant negative effect of mutant CBP.
Tanaka
Y
Y
Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, and CREST (Core Research for Evolutional Science and Technology) Research Project, JST (Japan Science and Technology Corporation), Tsukuba, 305-0074, Ibaraki, Japan.
Naruse
I
I
Hongo
T
T
Xu
M
M
Nakahata
T
T
Maekawa
T
T
Ishii
S
S
D000818:Animals; D050882:CREB-Binding Protein; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005313:Fetal Death / Q000235:genetics*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D020300:Intracranial Hemorrhages / Q000196:embryology / Q000235:genetics*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*
D009687:Nuclear Proteins; D015534:Trans-Activators; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse