Oh S Paul, Li En
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Dev Dyn. 2002 Jul;224(3):279-90. doi: 10.1002/dvdy.10103.
We have shown previously that mice deficient in the activin type IIB receptor (ActRIIB) exhibit right isomerism, which is characterized by mirror-image symmetrical right lungs, complex cardiac malformations, and hypoplasia of the spleen. These observations led us to hypothesize that the signaling of a TGF-beta family member by means of ActRIIB is necessary for the determination of the left-sidedness 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(-/-) 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(-/-) 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(-/-);ActRIIB(+/-) and iv(+/-);ActRIIB(-/-) 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-beta family member that signals through activin type II receptors, ActRIIA and ActRIIB, to specify the "left-sidedness." Nodal is the most likely candidate. We show here that the penetrance and severity of the right isomerism is significantly elevated in nodal(+/-); ActRIIB(-/-) mice, compared with ActRIIB(-/-) mice. Furthermore, the chimeric mice derived from nodal(-/-) ES cells displayed right isomerism, indistinguishable from that in (iv(-/-);ActRIIB(-/-)) mice. We propose that iv functions to establish asymmetric expression of nodal in a gene-dosage-sensitive manner and that nodal signals through the activin type II receptors to specify the left-sidedness by means of a threshold mechanism.
我们之前已经表明，缺乏激活素IIB型受体（ActRIIB）的小鼠表现出右位异构，其特征为镜像对称的右肺、复杂的心脏畸形以及脾脏发育不全。这些观察结果使我们推测，通过ActRIIB的TGF-β家族成员信号传导对于确定内脏器官的左侧性是必要的。为了验证这一假设，我们检查了同时携带ActRIIB和内脏反位（iv）基因突变的小鼠的侧位缺陷，因为iv（-/-）小鼠表现出一系列侧位缺陷，包括内脏反位、右位异构和左位异构。我们发现，所有iv和ActRIIB突变均为纯合子的小鼠都表现出右位异构。如持续性左下腔静脉、右心房异构和脾脏发育不全所示，双突变体中的右位异构表型也比ActRIIB（-/-）小鼠中的更严重。有趣的是，与携带单个基因突变的纯合子小鼠相比，iv（-/-）；ActRIIB（+/-）和iv（+/-）；ActRIIB（-/-）小鼠中右位异构的发生率也显著增加。ActRIIB和iv基因之间的遗传调节机制可能是iv调节通过激活素II型受体ActRIIA和ActRIIB发出信号的TGF-β家族成员的不对称表达，以确定“左侧性”。Nodal是最有可能的候选者。我们在此表明，与ActRIIB（-/-）小鼠相比，nodal（+/-）；ActRIIB（-/-）小鼠中右位异构的外显率和严重程度显著升高。此外，源自nodal（-/-）胚胎干细胞的嵌合小鼠表现出右位异构，与（iv（-/-）；ActRIIB（-/-））小鼠中的无异。我们提出，iv以基因剂量敏感的方式建立nodal的不对称表达，并且nodal通过激活素II型受体发出信号，通过阈值机制确定左侧性。
