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Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway

Simon D Bamforth1, José Bragança, Cassandra R Farthing

  • 1Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.

Nature Genetics
|October 12, 2004
PubMed

Insights

Mice lacking Cited2 develop cardiovascular and laterality defects due to impaired Nodal-Pitx2c signaling. These defects highlight a potential link between laterality and congenital heart disease.

Area of Science:

  • Developmental Biology
  • Genetics
  • Cardiovascular Research

Background:

  • Congenital cardiovascular defects are common, with Cited2 deficiency linked to septal and outflow tract malformations.
  • Laterality defects, such as isomerism and hyposplenia, are also observed in Cited2-deficient mice.

Purpose of the Study:

  • To investigate the role of Cited2 in laterality and cardiovascular development.
  • To elucidate the molecular mechanism underlying Cited2-deficiency-related defects.

Main Methods:

  • Analysis of Cited2(-/-) mice for laterality and cardiovascular phenotypes.
  • Investigation of Nodal target gene expression in the lateral plate mesoderm.
  • Chromatin immunoprecipitation and reporter assays to assess CITED2 and TFAP2 binding and activation of the Pitx2c promoter.

Main Results:

  • Cited2(-/-) mice exhibit laterality defects (right isomerism, abnormal cardiac looping, hyposplenia), which are genetically suppressed on a mixed background.
  • Absence of Cited2 leads to lack of Nodal target gene expression (Pitx2c, Nodal, Ebaf) in the left lateral plate mesoderm.
  • CITED2 and TFAP2 bind to the Pitx2c promoter and activate its transcription, indicating a direct regulatory role.

Conclusions:

  • An impaired Nodal-Pitx2c pathway is a unifying mechanism for cardiovascular malformations in Cited2(-/-) mice.
  • Cardiovascular malformations in Cited2 deficiency may represent the primary manifestation of a broader laterality defect.

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