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

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 ϩ/Ϫ ; Nodal ϩ/Ϫ 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.

Emerging roles for zic genes in early development

“…Thus, these Nodal-related signals are likely to be involved in activation of zic3 expression in the Xenopus organizer (Weber and Sokol, 2003). Consistent with this, zic3 is expressed in the involuting mesoderm at early gastrula stages (Kitaguchi et al, 2002) and in mice, the zic3 gene is required for correct patterning during gastrulation (Ware et al, 2006) prior to left-right axis formation.…”

“…As a result, subsequent Nodal expression in the lateral plate mesoderm becomes randomized, resulting in left-right patterning abnormalities (Purandare et al, 2002). Recently, an enhancer was identified in the promoter of the mouse Nodal gene that is responsive to Zic3, possibly by an indirect mechanism via Notch signaling (Ware et al, 2006). This region falls within a 2.7-kb enhancer that is located 9.5 kb upstream of the Nodal translation start site.…”

A human laterality disorder associated with recessiveCCDC11mutation

“…Other genes affecting the signal transduction of L-R asymmetry are the transforming growth factor β family member Nodal in which mutations account for ∼5% of HS patients,24 the Activin receptor, ACVR2B,25 and CFC1 26. These proteins are involved in isomerism probably via complex interactions with the Nodal signalling pathway 27. SIT/PCD1 and HS are usually discussed as two distinctive syndromes; however, certain overlap exists between them: 6.3% of the PCD1 patients have HS and respiratory complications.…”

Genetic Disturbances in Patients with Bodily Isomerism from a Single Center: Clinical Implications of Affected Genes and Potential Impact of Ciliary Dyskinesia

“…All have previously been described to be associated with ciliary dyskinesia in either mice or humans, and in some cases both. 16,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] We find it of significance, therefore, that a large proportion of affected genes are associated with not only isomerism, but also with ciliary dyskinesia. Previous studies have shown that over 40% of patients with isomerism also have ciliary dyskinesia.…”