Members of the transforming growth factor-β (TGF-β) superfamily act as multifunctional ligands to control the proliferation and differentiation of a variety of cell types

Members of the transforming growth factor-β (TGF-β) superfamily act as multifunctional ligands to control the proliferation and differentiation of a variety of cell types (Kingsley, 1994).Over the past decade, many have been shown to play essential roles during early embryogenesis in a broad range of animal species (Zhou et al., 1993; Weeks and Melton, 1987). A subfamily of these ligands, known as bone morphogenetic proteins (BMP) (Hogan, 1996), have been shown to be functionally conserved across distant species. In addition to the structural and functional conservation of the BMP ligands, the BMP receptor and signal transduction system are also highly conserved across species. Proper signaling requires complex formation of two distinct serine/threonine (ser/thr) kinase receptors, type I and type II. Upon ligand binding, a heteromeric complex of type I and type II receptor is formed. Type II receptor phosphorylates type I receptor at a specific sequence in the juxtatransmembrane region of the type I receptor, the (GS) box, resulting in signaling (Wrana et al., 1994). Activated type I receptor phosphorylates and activates intracellular component Smad protein that transduce its signal to the nucleus. (Massague, 1996; Heldin et al., 1997). In the nematode Caenorhabditis elegans, at least two TGFβ-like signaling pathways exist: the dauer larva formation (daf) and small (sma) pathways. The daf pathway regulates dauer larva formation in response to exposure of larval animals to starved or overcrowding conditions (Albert et al., 1981; Golden and Riddle, 1984). Dauer larva are stiff, motionless and appear to be developmentally arrested. Dauer formation-defective (daf-d) mutants fail to form dauer larvae under starved or overcrowding conditions. In contrast, constitutive dauer formation mutants (daf-c) are unable to resume a normal life cycle after the dauer-stimulating conditions are removed. Seven genes, daf-1, daf-3, daf-4, daf-5, daf-7, daf-8 and daf14 have been proposed to act in a common signaling pathway in the regulation of dauer larva formation (Thomas et al., 1993). daf-c genes, daf-1 (Georgi et al., 1990) and daf-4 (Estevez et al., 1993) encode type I and type II ser/thr kinase receptors for the TGF-β superfamily, respectively. DAF-4 has been shown to bind to BMP-2 and BMP-4 in mammalian cells (Estevez et al., 1993). More recently, DAF-7, also a member of the TGF-β superfamily, has been reported to negatively regulate dauer larva formation. Loss-of-function daf-7 mutants display a Daf-c phenotype (Ren et al., 1996). In the molecular analysis of daf-d genes, daf-3, which can suppress the phenotypes of daf-1, daf-4, daf-7, daf-8 and daf-14, has been shown to encode an inhibitory SMAD protein (Patterson et al., 1997). In contrast, the sma pathway appears to control nematode body length as well as ray formation in the male tail. Mutants of sma such as sma-2, sma-3 and sma-4 have shortened body length (Sma) and male tail abnormal (Mab) phenotypes (Baird and Emmons, 1990). sma-2, sma-3 and sma-4 have been shown to encode proteins similar to the 1337 Development 126, 1337-1347 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 DEV6385