THE SIGNALING PATHWAY MEDIATED BY THE TYPE IIB ACTIVIN RECEPTOR CONTROLS AXIAL PATTERNING AND LATERAL ASYMMETRY IN THE MOUSE

Vertebrate animals exhibit segmented axial skeletons and lateral asymm etry of the visceral organs, The segment identity of individual verteb rae is believed to be determined by a combination of functionally acti ve Hox genes that have defined expression boundaries along the anterop osterior axis (known as the axial Hox code). Disturbance of the Hox co de by ectopic expression or mutation of Hox genes often leads to homeo tic transformation of the vertebrae. Largely unknown, however, are til e signaling molecules that provide the positional cues for the precise establishment and maintenance of the Hox code. In this study rye show that disruption of the type IIB activin receptor (ActRIIB) by gene ta rgeting results in altered expression of multiple Hox genes and abnorm al patterning of the vertebrae, similar to but severer than retinoic a cid (RA)-induced anterior transformation. We further show that RA and ActRIIB mutation have synergistic effects on vertebral patterning. Act ivin, Vg-1 and, type II activin receptors have been implicated in regu lation of lateral asymmetry during chick and Xenopus development. We s how here that the ActRIIB(-/-) mice die after birth with complicated c ardiac defects including randomized heart position, malposition of the great arteries, and ventricular and atrial septal defects. In additio n, the heart anomalies are associated with right pulmonary isomerism a nd 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 patter ning both anteroposterior and left-right axes in vertebrate animals.