Studying TGF-beta superfamily signaling by knockouts and knockins

The transforming growth factor beta (TGF-beta) superfamily has profound eff ects on many aspects of animal development. In the last decade, our laborat ory and others have performed in vivo functional studies on multiple compon ents of the TGF-beta superfamily signal transduction pathway, including ups tream ligands. transmembrane receptors, receptor-associated proteins and do wnstream Smad proteins. We have taken gene knockout approaches to generate null alleles of the genes of interest, as well as a gene knockin approach t o replace the mature region of one TGF-beta superfamily ligand with another . We found that activin betaB. expressed in the spatiotemporal pattern of a ctivin betaA, can function as a hypomorphic allele of activin betaA and res cue the craniofacial defects and neonatal lethal phenotype of activin betaA -deficient mice. With the knockout approach. we have shown that the express ion pattern of a component in the TGF-beta superfamily signal transduction cascade does not necessarily predict its in vivo function. Two liver-specif ic activins, activin betaC and activin betaE are dispensable for liver deve lopment, regeneration and function, whereas ubiquitously expressed Smad5 ha s specific roles in the development of multiple embryonic and extraembryoni c tissues. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.