Smads and cell fate: distinct roles in specification, development, and tumorigenesis in the testis

According to the World Health Organization, a fertile man typically has a sperm count of 15 million per milliliter of semen. This spermatogenic capacity is determined by appropriate specification, proliferation, differentiation, and maturation of somatic and germ cells, events that begin during fetal development and continue throughout adulthood. These processes are orchestrated by the integration of signaling inputs from hormones and growth factors, including those of several transforming growth factor beta (TGFβ) superfamily ligands. This review summarizes current knowledge of the Smad proteins, which serve functions central to fertility by transducing TGFβ superfamily ligand signals in the testis. The importance of regulated Smad expression and differential utilization in signal transduction for fine-tuning cellular responses to ligands is discussed. We evaluate how primary cell culture studies and analyses of genetically modified mice have revealed distinct roles for specific Smads in primordial germ cell lineage specification, in determining the pace of testicular development and in controlling testicular tumorigenesis. This review also addresses the new insights gained from examining heterozygous mice that exhibit intriguing gene-dosage effects, outcomes that provide a new understanding of how TGFβ superfamily ligands influence testis development and function. Finally, we consider the growing understanding that Smads mediate cross-talk with hormones to play a central role in determining male fertility and reproductive health.