Polypeptides of the type.. fi transforming growth factor (TGFfi) superfamily play a series of critical roles in development, dilI~ rentiation and tissue repair (Kingsley, 1994), and have begun to receive increasing attention for their potential involvement in cardiovascular organogenesis and disease (MacLellan et al., 1993). The 25 or so members of this family share a common structural element, seven cysteine residues in the C4erminus of the mature protein, which form a characteristic" cysteine knot"; in addition, one cysteine participates in homo-or heterodimerization (Schlunneger and Grutter, 1992). Initially, proteins encoded by the superfamily contain an amino-terminal signal sequence for export from the cell, and a pro-peptide domain of variable size. This precursor is cleaved at a dibasic or RXXR site, to release the biologically active, carboxy-tenninal peptide. Mutations in the pro-peptide domain of TGFfi have demonstrated that this region is necessary for proper folding, stability, and secretion (Sha et al., 1991). Based upon sequence homologies among the mature peptides, the TGFfi superfamily has been subdivided, in turn, into several discrete subfamilies:• The prototype for these is the TGFfi family itself, comprising TGFfil,-fi2, and-fi3, as well as the proteins TGFfi4 in avians, and TGFfi5 in Xen-opus. The three mammalian TGFfi isolbrms which have been identified share approximately 70% sequence homology at the amino acid level (Roberts and Spore,] 990), and in most cell systems tested thus far--though not all--have indistinguishable biological activities. However, their spatial distributions or patterns of expression are quite distinct in both the embryo and the adult (Akhurst et al., 1990; Millan et al., 199: 1: Dickson et al., 1993).. The activin family consists of inhibin fiA and inhibin fiB, which ihomodimerize (to form activin A and activin B, respectively), or associate as heterodimers with the more distant peptide, inhibin c~, to lbrm inhibin A (~/fiA) or B (~/fiB). The activins/inhibins have important functions in pineal and gonadal differentiation (Vale et al., 1990), and activin A functions as a potent mesoderm inducer in early amphibian gastrulation (Smith et al., 1990; Thomsen et al., 1990; van den Eijnden-van Raaij et al., 1990).

, Cognate members of the dpp/Vg-related subfamily are decapentaplegic and VgJ, two genes encoding proteins that mediate morphogenesis. This complex class of proteins encompasses@ and 60A from Drosophila, Vgl from Xenopus, numerous bone morphogenic proteins (BMP 2-8), growth and differentiation factor-I (GI) F-]), GDF-3/Vgr2, nodal, and dorsalin; more distantly related members include Mfillerian inhibitory substance, GDF9, GDNF and inhibin c~(Kingsley, 1994). The Vgl genel product is spatially restricted to the vegetal pole of the oocyte, is believed to play an important role in early Xeltopus development, and is sufficient to provoke the formation of a dorsal axis and mesoderm, including heart, in cells of the Xi, nopus animal