Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos.
Histone acetyltransferases (HATs) are important to gene activation, altering chromatin structures to facilitate association of transcription proteins with gene promoters. The functions of individual HATs in mammalian developmental are not well defined. Our previous studies demonstrated that Gcn5, a prototypical HAT, is required for mesodermal maintenance in early embryos. Homozygous Gcn5 null embryos die soon after gastrulation, preventing determination of Gcn5 functions later during development. We report here the creation of a Gcn5(flox(neo)) allele, which is only partially functional and gives rise to a hypomorphic phenotype. Mice homozygous for this allele had an increased risk of cranial neural tube closure defects (NTDs) and exencephaly. These defects were found at an even greater penetrance in Gcn5(flox(neo)/Delta) embryos. These results indicate that normal levels of Gcn5 expression are critical for neural tube closure in mice and predict that mutations in this HAT may be associated with increased risk of NTDs in humans.
Lin
Wenchu
W
Program in Genes and Development, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Zhang
Zhijing
Z
Srajer
Geraldine
G
Chen
Yi Chun
YC
Huang
Maosheng
M
Phan
Huy M
HM
Dent
Sharon Y R
SY
D000483:Alleles; D000818:Animals; D019521:Body Patterning; D016923:Cell Death; D049109:Cell Proliferation; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054259:Neural Tube / Q000502:physiology*; D009436:Neural Tube Defects / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D005492:Folic Acid; D053823:Hedgehog Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C465570:Shh protein, mouse