Genetic analysis of the mammalian transforming growth factor-β superfamily

Members of the TGF-beta superfamily, which includes TGF-betas, 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-beta 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.