Smads and early developmental signaling by the TGFbeta superfamily.

Members of the transforming growth factor b (TGFb) superfamily of peptide growth factors regulate a broad range of cellular functions, including proliferation, apoptosis, extracellular matrix secretion and adhesion, terminal differentiation, and specification of developmental fate (Roberts and Sporn 1993; Wall and Hogan 1994; Moses and Serra 1996). Although regulation of each of these functions by TGFb superfamily factors is important throughout embryonic development, it is the potency of these factors in regulating developmental fate that has been the focus of recent excitement among embryologists. This has been primarily because of indications in both vertebrate and invertebrate model systems that TGFbs can serve as morphogens, acting across developing tissues in a graded fashion to specify a patterned array of cell fates (Gurdon et al. 1994; Nellen et al. 1996; Neumann and Cohen 1997). A defining feature of morphogens is their ability to specify multiple cell types over a range of concentrations. This capacity has been demonstrated for several members of the TGFb superfamily in early Xenopus embryos (Green and Smith 1990; Dosch et al. 1997; Wilson et al. 1997) and for the bone morphogenetic protein (BMP) homolog decapentaplegic (dpp) in the early Drosophila embryo and wing disc (Gelbart 1989; Ferguson and Anderson 1992; Wharton et al. 1993; Lecuit et al. 1996; Nellen et al. 1996). The intracellular mechanisms by which ligand dose can be transduced into multiple developmental fates is therefore a current focus of interest for understanding TGFbs as morphogens. A second striking feature of TGFb superfamily signals is the variety of effects they can evoke, contingent on the developmental history of the responding cell. For example, at the gastrula stage, BMP2 can specify frog blastomeres as epidermal rather than neural progenitors (Wilson et al. 1997); at later stages it can specify dorsoventral pattern in the neural tube (for review, see Tanabe and Jessell 1997), neural crest (NC) cells to form neuronal rather than Schwann cells (for review, see Mehler et al. 1997), and apoptotic patterning of the NC during rhombomere segmentation (Graham and Lumsden 1996). How the developmental history of a particular cell intersects with an instructive signal from a TGFb superfamily ligand to generate a cell type-specific developmental decision is therefore a second critical question in understanding how these ligands function in developmental patterning. A third central issue, closely tied to the first two, is how other signaling pathways that participate in developmental patterning interact with TGFb superfamily signals. Over the past 10 years considerable progress has been made in understanding where and when different TGFb superfamily ligands signal in embryos and defining characteristic transcriptional responses that mark their effects. Understanding the molecular basis for patterning, however, will also require a knowledge of how the intracellular signal transduction of TGFbs integrates ligand dose, developmental history, and signals from other pathways to generate the complex set of responses observed during embryogenesis. Until recently, very little has been known about how TGFb superfamily signals are transduced intracellularly. This situation has changed rapidly over the past 3 years, however, with the discovery and characterization of the Smad family of gene products as transducers of TGFb superfamily signals (for review, see Derynck and Feng 1997; Heldin et al. 1997; Attisano and Wrana 1998; Massagué 1998). Although our understanding of how Smads mediate cell type-specific transcriptional regulation is still incomplete, characterization of these signal transducers has begun to provide a molecular framework within which to investigate in detail how the TGFb superfamily of factors regulates complex patterns of cell specification. In addition to providing our first picture of how TGFb signals directly regulate transcription, studies of Smad regulation have begun to provide clues as to how cells integrate multiple signals from both TGFb and non-TGFb signaling pathways. Recent work on the extracellular regulation of BMPs during embryogenesis has provided a dramatic advance in the understanding of BMP-dependent patterning mechanisms conserved between vertebrates and invertebrates (Holley et al. 1995; Piccolo et al. 1996; Zimmerman et al. 1996); recent advances in understanding intracellular regulation by TGFbs provides new opportunities for examining their function in patterning at multiple steps in embryogenesis. TGFb superfamily signal transduction has been the subject of numerous reviews over the past 2 years (see above). This review will provide a relatively cursory E-MAIL mwhitman@warren.med.harvard.edu; FAX (617) 432-1144.