The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse.

Abstract

Vertebrate animals exhibit segmented axial skeletons and lateral asymmetry of the visceral organs. The segment identity of individual vertebrae is believed to be determined by a combination of functionally active Hox genes that have defined expression boundaries along the anteroposterior axis (known as the axial Hox code). Disturbance of the Hox code by ectopic expression or mutation of Hox genes often leads to homeotic transformation of the vertebrae. Largely unknown, however, are the signaling molecules that provide the positional cues for the precise establishment and maintenance of the Hox code. In this study we show that disruption of the type IIB activin receptor (ActRIIB) by gene targeting results in altered expression of multiple Hox genes and abnormal patterning of the vertebrae, similar to but severer than retinoic acid (RA)-induced anterior transformation. We further show that RA and ActRIIB mutation have synergistic effects on vertebral patterning. Activin, Vg-1 and, type II activin receptors have been implicated in regulation of lateral asymmetry during chick and Xenopus development. We show here that the ActRIIB -/-mice die after birth with complicated cardiac defects including randomized heart position, malposition of the great arteries, and ventricular and atrial septal defects. In addition, the heart anomalies are associated with right pulmonary isomerism and splenic abnormalities, recapitulating the clinical symptoms of the human asplenia syndrome. These findings provide genetic evidence that the ActRIIB-mediated signaling pathway plays a critical role in patterning both anteroposterior and left-right axes in vertebrate animals.[Key Words." Activin/BMP; serine/threonine kinase receptor; axial skeleton; lateral asymmetry; asplenia syndrome]

Genetic interactions between activin type IIB receptor and Smad2 genes in asymmetrical patterning of the thoracic organs and the development of pancreas islets

“…However, as we expected, none of the ActRIIB Ϫ/Ϫ Smad2 ϩ/Ϫ mice were recovered at the weaning stage, as shown in Table 1. Because the lethality of the mice homozygous for ActRIIB was 74%, consistent with previous observation (Oh and Li, 1997), the loss of one allele of Smad2 on ActRIIB homozygous background resulted in increased lethality, showing apparent genetic interactions of Smad2 and ActRIIB. It is noted that the ActRIIB ϩ/Ϫ Smad2 ϩ/Ϫ mice are less viable than expected, further suggesting genetic interaction between ActRIIB and Smad2.…”

“…Detailed procedures for the generation of ActRIIB and Smad2 knockout mice are described elsewhere (Oh and Li, 1997;Nomura and Li, 1998). ActRIIB ϩ/Ϫ mice were crossed with Smad2 ϩ/Ϫ mice on a 129SV/C57BL6 hybrid background.…”

“…The criteria for cardiac defects and right pulmonary isomerism used in this study were previously described (Oh and Li, 1997;Oh et al, 2002). Briefly, outflow tract defects were recognized when the ascending Ao was placed anterior to the pulmonary trunk (PT).…”

“…The type II activin receptors, ActRIIA and ActRIIB, have been shown to play important roles in axial patterning (Oh and Li, 1997;Song et al, 1999;Oh et al, 2002) and later in organ development (Oh and Li, 1997;Kim et al, 2000). The ActRIIA-deficient mice exhibit craniofacial defects including hypoplasia of mandibles, reduced fertility, and gastrulation defects (Matzuk et al, 1995;Song et al, 1999).…”

“…On the other hand, the ActRIIB-deficient mice displayed multiple patterning defects, including complex cardiac defects, pulmonary isomerism (disturbance of left-right asymmetry), kidney agenesis, and axial patterning such as anterior transformation of the axial skeleton. Seventy percent of the ActRIIB Ϫ/Ϫ mice on hybrid background die after birth owing to right isomerism, which is characterized by mirror-image symmetrical right lungs, and complex cardiac malformations (Oh and Li, 1997). Although disruption of individual type II activin receptors results in nonoverlapping phenotypes, most of the phenotypes described for ActRIIA or ActRIIB mice exhibit incomplete penetrance and these two receptors show functional compensation during such patterning events.…”