Defective extraembryonic angiogenesis in mice lacking LBP-1a, a member of the grainyhead family of transcription factors

Mol Cell Biol. 2004 Aug;24(16):7113-29. doi: 10.1128/MCB.24.16.7113-7129.2004.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / anatomy & histology
  • Embryo, Mammalian / physiology*
  • Female
  • Fetal Growth Retardation
  • Gene Targeting
  • Genetic Complementation Test
  • Gestational Age
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Physiologic*
  • Placenta / blood supply*
  • Placenta / cytology
  • Placenta / metabolism
  • Placenta / pathology
  • Pregnancy
  • RNA-Binding Proteins
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • DNA-Binding Proteins
  • RNA-Binding Proteins
  • Transcription Factors
  • UBP1 protein, human
  • Vascular Endothelial Growth Factor Receptor-2