Genetic Analysis of the Mammalian Transforming Growth Factor-β Superfamily

0163-769X/02/$20.00/0 Printed in U.S.A. Endocrine Reviews 23(6):787– 823 Copyright © 2002 by The Endocrine Society doi: 10.1210/er.2002-0003 Genetic Analysis of the Mammalian Transforming Growth Factor-␤ Superfamily HUA CHANG, CHESTER W. BROWN, AND MARTIN M. MATZUK Departments of Pathology (H.C., M.M.M.), Molecular and Human Genetics (C.W.B., M.M.M.), Molecular and Cellular Biology (M.M.M.), and Pediatrics (C.W.B.), and Program in Developmental Biology (H.C., M.M.M.), Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030 Members of the TGF-␤ superfamily, which includes TGF-␤s, growth differentiation factors, bone morphogenetic proteins, activins, inhibins, and glial cell line-derived neurotrophic factor, are synthesized as prepropeptide precursors and then processed and secreted as homodimers or heterodimers. Most ligands of the family signal through transmembrane serine/ threonine kinase receptors and SMAD proteins to regulate cellular functions. Many studies have reported the characterization of knockout and knock-in transgenic mice as well as humans or other mammals with naturally occurring genetic mutations in superfamily members or their regulatory proteins. These investigations have revealed that TGF-␤ superfamily ligands, receptors, SMADs, and upstream and downstream regulators function in diverse developmental and physiological pathways. This review attempts to collate and integrate the extensive body of in vivo mammalian studies produced over the last decade. (Endocrine Reviews 23: 787– 823, 2002) I. Introduction H. Nervous system development I. Other organ systems II. Components of the TGF-␤ Superfamily Signal Transduction Pathway A. Ligands B. Receptors C. SMAD proteins D. Other components in the TGF-␤ superfamily signaling cascade III. TGF-␤ Superfamily Signaling and Development A. Early postimplantation mouse embryonic and extraembryonic development B. Heart development C. Left-right asymmetry D. Vasculogenesis and angiogenesis E. Craniofacial development F. Skeletal morphogenesis G. Body composition and growth IV. TGF-␤ Superfamily Signaling and Reproduction A. Function of MIS signaling pathways in sexual differentiation B. Primordial germ cell development C. Gonadal development V. Perspectives and Future Directions A. Promiscuity within the family B. Intracellular signaling C. Superfamily signaling and human disease I. Introduction T HE TGF-␤ SUPERFAMILY is a large group of extracellular growth factors controlling many aspects of development (1–5). Homo- or hetero-dimers of the TGF-␤ family ligands bind to and activate two types of transmembrane serine/threonine kinase receptors, which then stimulate downstream regulatory SMAD proteins to localize from the cytoplasm to the nucleus where they can function as transcriptional regulators (3, 6 – 8). TGF-␤ superfamily signaling is regulated at multiple levels, including extracellular binding and processing of TGF-␤ superfamily ligands and intracellular interactions of the receptors. Gene inactivation studies in mice during the past decade have greatly expanded our understanding of TGF-␤ superfamily signaling in animal development, and many of these studies have been summarized in the abovementioned reviews (1, 2). In this review, we will focus on the latest progress in this field, with emphasis on the roles of TGF-␤ superfamily signaling in embryonic development, reproduction, and tumor formation. Abbreviations: ActRIB, Activin receptor type IB; ACVR2, activin receptor type IIA; ALK, activin receptor-like kinase; AV, atrial-ventricular; BMP, bone morphogenetic protein; Bmpr, BMP receptor; bp, brachypodism; CBP, CREB binding protein; CDMP, cartilage-derived morphogenetic protein; DPC4, deleted in pancreatic carcinoma locus 4; dpp, decapentaplegic; E, embryonic day; ES, embryonic stem; FecB, Booroola fecundity gene; FGF, fibroblast growth factor; FoxH1, forkhead or winged helix DNA-binding protein 1; GDF, growth differentiation factor; GDNF, glial cell line-derived neurotrophic factor; HTC, HunterThompson acromesomelic chondrodysplasia; Inhba, activin/inhibin ␤A; Inhbb, activin/inhibin ␤B; InhBP, inhibin-binding protein; LAP, latency associated peptide; LPM, lateral plate mesoderm; MAD, mothers against dpp; MEE, medial edge epithelium; MH1, MAD homologous region 1; MIS, Müllerian inhibiting substance; PFP, putative ventral floor plate; PGC, primordial germ cells; PTX3, pentraxin; R-SMAD, receptor-regulated SMAD; SARA, SMAD anchor for receptor activation; SF-1, steroidogenic factor-1; SHH, sonic hedgehog; SMA DIP1, SMAD-interacting protein 1; SNIP1, SMAD nuclear interacting protein 1; TAB1, TAK1binding protein 1; TAK1, TGF-␤-activating kinase-1; T␤RI, TGF-␤ type I receptor; TGIF, transforming growth interacting factor; TRIP-1, TGF-␤ type II receptor-interacting protein; TSP-1, thrombospondin 1. 787 788 Endocrine Reviews, December 2002, 23(6):787– 823 II. Components of the TGF-␤ Superfamily Signal Transduction Pathway A. Ligands The TGF-␤ superfamily consists of more than 35 members in vertebrates, including TGF-␤s, BMPs (bone morphogenetic proteins), GDFs (growth differentiation factors), activins, inhibins, MIS (Müllerian inhibiting substance), Nodal, and leftys (2, 9, 10; Fig. 1). The TGF-␤ family ligands are translated as prepropeptide precursors with an N-terminal signal peptide followed by the prodomain and the mature domain. Six to nine conserved cysteine residues in the mature domain form intra- and intermolecular disulfide bonds characteristic of this family of proteins (3, 10, 11). Several members of the family (i.e., GDF-9, BMP-15, GDF-3, lefty-1, and lefty-2) have a substitution of a serine for the cysteine normally involved in intermolecular disulfide bond forma- Chang et al. • Mammalian TGF-␤ Superfamily tion. Therefore, although dimers of most family members are held together covalently, the proteins with this substitution would be expected to be noncovalently associated and possibly more labile. TGF-␤s are secreted as biologically latent forms (12, 13). The activity of the mature domain of the TGF-␤ ligand is masked by the propeptide, LAP (latency associated peptide), which is cleaved from the mature domain by a furin-like endoproteinase during secretion but remains associated with the mature domain via noncovalent interactions (14). Dissociation from LAP activates the TGF-␤ subfamily of ligands and possibly other members of the superfamily. The extracellular matrix protein thrombospondin 1 (TSP-1; Refs. 15 and 16), as well as integrin ␣v␤6 (17), also mediates TGF-␤ activation under physiological conditions. Other mechanisms, such as proteolysis (16, 17), may also be involved in the activation of TGF-␤ ligands in vivo (18). FIG. 1. TGF-␤ superfamily. Amino acid sequences of the carboxyl-terminal polypeptides of the mouse TGF-␤ superfamily members (and human BMP-8) were aligned using the PILEUP program (Genetics Computer Group, Madison, WI). Mouse and human sequ (...truncated)