Heart defects in X-linked heterotaxy: Evidence for a genetic interaction of Zic3 with the Nodal signaling pathway

Stephanie Ware, Karine G. Harutyunyan, John W. Belmont

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

The complex cardiac defects that occur in heterotaxy result from abnormal left-right patterning. Mutations in the zinc finger transcription factor ZIC3 cause X-linked heterotaxy, HTX1. We previously have generated a targeted deletion of the murine Zic3 locus and demonstrated that these knockout mice correctly model HTX1. Fifty percent of Zic3 null embryos have cardiac looping anomalies at embryonic day 10.5 to 14.5, with ventral looping and sinistral looping as the predominant phenotypes. The penetrance of these phenotypes is increased in mice that are also haploinsufficient for Nodal. Zic3+/-; Nodal +/- compound heterozygous mice are born in significantly reduced numbers (P = 0.0001), indicating a genetic interaction between the loci. Furthermore, an upstream Nodal enhancer is responsive to Zic3 in both Xenopus and mouse. These studies provide evidence that Zic3 interacts genetically with Nodal in left-right patterning and subsequent cardiac development and delineate a critical Zic3-responsive enhancer required for mediating Nodal expression at the node.

Original languageEnglish (US)
Pages (from-to)1631-1637
Number of pages7
JournalDevelopmental Dynamics
Volume235
Issue number6
DOIs
StatePublished - Jun 2006
Externally publishedYes

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Phenotype
Penetrance
Zinc Fingers
Xenopus
Knockout Mice
Transcription Factors
Embryonic Structures
Mutation

Keywords

  • Cardiac development
  • Heterotaxy
  • Left-right patterning
  • Nodal
  • Outflow tract
  • Zic3

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

Cite this

Heart defects in X-linked heterotaxy : Evidence for a genetic interaction of Zic3 with the Nodal signaling pathway. / Ware, Stephanie; Harutyunyan, Karine G.; Belmont, John W.

In: Developmental Dynamics, Vol. 235, No. 6, 06.2006, p. 1631-1637.

Research output: Contribution to journalArticle

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