Transcription Factor Sp3 Knockout Mice Display Serious Cardiac Malformations

Mol Cell Biol. 2007 Dec;27(24):8571-82. doi: 10.1128/MCB.01350-07. Epub 2007 Oct 8.

Abstract

Mice lacking the zinc finger transcription factor specificity protein 3 (Sp3) die prenatally in the C57BL/6 background. To elucidate the cause of mortality we analyzed the potential role of Sp3 in embryonic heart development. Sp3 null hearts display defective looping at embryonic day 10.5 (E10.5), and at E14.5 the Sp3 null mutants have developed a range of severe cardiac malformations. In an attempt to position Sp3 in the cardiac developmental hierarchy, we analyzed the expression patterns of >15 marker genes in Sp3 null hearts. Expression of cardiac ankyrin repeat protein (Carp) was downregulated prematurely after E12.5, while expression of the other marker genes was not affected. Chromatin immunoprecipitation analysis revealed that Sp3 is bound to the Carp promoter region in vivo. Microarray analysis indicates that small-molecule metabolism and cell-cell interactions are the most significantly affected biological processes in E12.5 Sp3 null myocardium. Since the epicardium showed distension from the myocardium, we studied expression of Wt1, a marker for epicardial cells. Wt1 expression was diminished in epicardium-derived cells in the myocardium of Sp3 null hearts. We conclude that Sp3 is required for normal cardiac development and suggest that it has a crucial role in myocardial differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / pathology
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Genome
  • Heart / embryology
  • Heart Defects, Congenital / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Proteins
  • Nuclear Proteins / genetics
  • Organ Size
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Repressor Proteins / genetics
  • Sp3 Transcription Factor / deficiency*
  • Sp3 Transcription Factor / genetics
  • Sp3 Transcription Factor / metabolism*

Substances

  • Ankrd1 protein, mouse
  • Biomarkers
  • Muscle Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Sp3 Transcription Factor