Mouse t-complex protein 11 is important for progressive motility in sperm†.

The t-complex is defined as naturally occurring variants of the proximal third of mouse chromosome 17 and has been studied by mouse geneticists for decades. This region contains many genes involved in processes from embryogenesis to sperm function. One such gene, t-complex protein 11 (Tcp11), was identified as a testis-specific gene whose protein is present in elongating spermatids.

Genome engineering uncovers 54 evolutionarily conserved and testis-enriched genes that are not required for male fertility in mice.

Gene-expression analysis studies from Schultz et al. estimate that more than 2,300 genes in the mouse genome are expressed predominantly in the male germ line. As of their 2003 publication [Schultz N, Hamra FK, Garbers DL (2003) Proc Natl Acad Sci USA 100(21):12201-12206], the functions of the majority of these testis-enriched genes during spermatogenesis and fertilization were largely unknown.

Disrupting the male germ line to find infertility and contraception targets.

Genetically-manipulated mouse models have become indispensible for broadening our understanding of genes and pathways related to male germ cell development. Until suitable in vitro systems for studying spermatogenesis are perfected, in vivo models will remain the gold standard for inquiry into testicular function. Here, we discuss exciting advances that are allowing researchers faster, easier, and more customizable access to their mouse models of interest.

Loss of smad4 in Sertoli and Leydig cells leads to testicular dysgenesis and hemorrhagic tumor formation in mice.

As the central component of canonical TGFbeta superfamily signaling, SMAD4 is a critical regulator of organ development, patterning, tumorigenesis, and many other biological processes. Because numerous TGFbeta superfamily ligands are expressed in developing testes, there may exist specific requirements for SMAD4 in individual testicular cell types. Previously, we reported that expansion of the fetal testis cords requires expression of SMAD4 by the Sertoli cell lineage.

GASZ promotes germ cell derivation from embryonic stem cells.

Primordial germ cells (PGCs) are the first germ-line population that forms from the proximal epiblast of the developing embryo. Despite their biological importance, the regulatory networks whereby PGCs arise, migrate, and differentiate into gametes during embryonic development remains elusive, largely due to the limited number of germ cells in the early embryo. To elucidate the molecular mechanisms that govern early germ cell development, we utilized an in vitro differentiation model of embryonic stem cells (ESCs) and screened a series of candidate genes with specific expression in the adult reproductive organs.

Testicular somatic cells, not gonocytes, are the major source of functional activin A during testis morphogenesis.

Proper development of the seminiferous tubules (or testis cords in embryos) is critical for male fertility. Sertoli cells, somatic components of the seminiferous tubules, serve as nurse cells to the male germline, and thus their numbers decide the quantity of sperm output in adulthood. We previously identified activin A, the protein product of the activin βA (Inhba) gene, as a key regulator of murine Sertoli cell proliferation and testis cord expansion during embryogenesis.

Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion.

Formation of tubular structures relies upon complex interactions between adjacent epithelium and mesenchyme. In the embryonic testes, dramatic compartmentalization leads to the formation of testis cords (epithelium) and the surrounding interstitium (mesenchyme). Sertoli cells, the epithelial cell type within testis cords, produce signaling molecules to orchestrate testis cord formation.

Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development.

Interactions between adjacent epithelial and mesenchymal tissues represent a highly conserved mechanism in embryonic organogenesis. In particular, the ability of the mesenchyme to instruct cellular differentiation of the epithelium is a fundamental requirement for the morphogenesis of tubular structures such as those found in the kidneys, lungs, and the developing male reproductive system. Once the tubular structure has formed, it receives signals from the mesenchyme, which can control proliferation, patterning, and differentiation of the epithelium inside the tube.

Essential roles of inhibin beta A in mouse epididymal coiling.

Testis-derived testosterone has been recognized as the key factor for morphogenesis of the Wolffian duct, the precursor of several male reproductive tract structures. Evidence supports that testosterone is required for the maintenance of the Wolffian duct via its action on the mesenchyme. However, it remains uncertain how testosterone alone is able to facilitate formation of regionally specific structures such as the epididymis, vas deferens, and seminal vesicle from a straight Wolffian duct.