Defective extraembryonic angiogenesis in mice lacking LBP-1a, a member of the grainyhead family of transcription factors.
LBP-1a and CP2 are ubiquitously expressed members of the grainyhead transcription factor family, sharing significant sequence homology, a common DNA binding motif, and modulating a range of key regulatory and structural genes. We have reported previously that CP2-null mice are viable with no obvious abnormality. LBP-1a provides redundant function in this context. We show here that mice lacking LBP-1a expression develop intrauterine growth retardation at embryonic day 10.5, culminating in death 1 day later. No focal intraembryonic cause for this CP2-independent defect is evident. In contrast, a significant reduction in the thickness of the labyrinthine layer of the placenta is observed in LBP-1a(-/-) animals. However, expression of trophoblast differentiation markers is unperturbed in this context, and complementation studies utilizing tetraploid wild-type cells failed to rescue or ameliorate the LBP-1a(-/-) phenotype, excluding a primary trophoblast defect. An explanation for these observations is provided by the prominent angiogenic defect observed in the mutant placentas. LBP-1a(-/-) allantoic blood vessels fail to penetrate deeply and branch into the complex embryonic vasculature characteristic of the normal placenta. Interestingly, a similar defect in angiogenesis is observed in the yolk sac vasculature, primary endothelial cell-lined capillary tubes, although present, failed to connect into a characteristic intricate vascular network. Collectively, these results demonstrate that LBP-1a plays a critical role in the regulation of extraembryonic angiogenesis.
Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Vishwas
V
Parekh
Amy
A
McEwen
Virginia
V
Barbour
Yutaka
Y
Takahashi
Jerold E
JE
Rehg
Stephen M
SM
Jane
John M
JM
Cunningham
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000033:anatomy & histology / Q000502:physiology*; D005260:Female; D005317:Fetal Growth Retardation; D018390:Gene Targeting; D005816:Genetic Complementation Test; D005865:Gestational Age; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D010920:Placenta / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C085968:UBP1 protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2