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These observations led us to hypothesize that the signaling of a TGF\u2010\u03b2 family member by means of ActRIIB is necessary for the determination of the left\u2010sidedness of the visceral organs. To test this hypothesis, we examined laterality defects in mice carrying mutations in both ActRIIB and inversus viscerum (iv) genes, because iv<jats:sup>\u2010\/\u2010<\/jats:sup> mice display a spectrum of laterality defects, including situs inversus, right isomerism, and left isomerism. We found that all mice homozygous for both iv and ActRIIB mutations displayed the right isomerism. The phenotype of right isomerism in the double mutants was also more severe than that in ActRIIB<jats:sup>\u2010\/\u2010<\/jats:sup> mice as shown by persistent left inferior vena cava, right atrial isomerism, and hypoplasia of spleen. Interestingly, the incidence of right isomerism also increased significantly in iv<jats:sup>\u2010\/\u2010<\/jats:sup>;ActRIIB<jats:sup>+\/\u2010<\/jats:sup> and iv<jats:sup>+\/\u2010<\/jats:sup>;ActRIIB<jats:sup>\u2010\/\u2010<\/jats:sup> mice compared with homozygous mice carrying either of single gene mutations. A mechanism of the genetic modulation between ActRIIB and iv genes may be that iv modulates the asymmetric expression of a TGF\u2010\u03b2 family member that signals through activin type II receptors, ActRIIA and ActRIIB, to specify the \u201cleft\u2010sidedness.\u201d Nodal is the most likely candidate. We show here that the penetrance and severity of the right isomerism is significantly elevated in nodal<jats:sup>+\/\u2010<\/jats:sup>; ActRIIB<jats:sup>\u2010\/\u2010<\/jats:sup> mice, compared with ActRIIB<jats:sup>\u2010\/\u2010<\/jats:sup> mice. Furthermore, the chimeric mice derived from nodal<jats:sup>\u2010\/\u2010<\/jats:sup> ES cells displayed right isomerism, indistinguishable from that in (iv<jats:sup>\u2010\/\u2010<\/jats:sup>;ActRIIB<jats:sup>\u2010\/\u2010<\/jats:sup>) mice. We propose that iv functions to establish asymmetric expression of nodal in a gene\u2010dosage\u2013sensitive manner and that nodal signals through the activin type II receptors to specify the left\u2010sidedness by means of a threshold mechanism. \u00a9 2002 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/dvdy.10103","type":"journal-article","created":{"date-parts":[[2002,10,6]],"date-time":"2002-10-06T07:34:39Z","timestamp":1033889679000},"page":"279-290","source":"Crossref","is-referenced-by-count":23,"title":["Gene\u2010dosage\u2010sensitive genetic interactions between inversus viscerum (<i>iv<\/i>), <i>nodal<\/i>, and activin type IIB receptor (<i>ActRIIB<\/i>) genes in asymmetrical patterning of the visceral organs along the left\u2010right axis"],"prefix":"10.1002","volume":"224","author":[{"given":"S. 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