Drivers of Germ Cell Maturation

Abstract

Spermatogenesis requires progression of germ line stem cells through a precisely ordered differentiation pathway to form spermatozoa. Diverse and dynamic signals from the transforming growth factor-beta (TGF-beta) superfamily influence many stages of germ cell development. For example, interactions between several TGF-beta superfamily ligands (bone morphogenetic proteins, activin, and glial-derived neurotrophic growth factor [GDNF]) appear to govern the onset of spermatogenesis, and we are exploring how germ cells interpret these competing signals. We examined the in vivo impact of activin on testis development using two mouse models, the inhba-/- mouse (which lacks the gene encoding the activin A subunit and dies at birth) and BK mice, with inhbb (encoding the activin betaB subunit) replacing inhba (which survive to adulthood and show delayed fertility onset in males). Distinct effects on Sertoli cell and germ cell populations during fetal and early postnatal development were measured. We recognize that specific proteins, including downstream targets of TGF-beta signals, such as Smads, must move into the nucleus to implement the gene transcription changes required for development. We hypothesized that changes at the level of cellular nuclear transport machinery may be required to mediate this. Examination of proteins involved in classical nuclear import, the importins, revealed that each importin has a developmentally regulated expression pattern in male germ cells. Because each importin binds a selected range of cargo proteins and mediates their nucleocytoplasmic passage, our findings suggest that each importin ferries cargo required for discrete stages of spermatogenesis.

Activin A Balances Sertoli and Germ Cell Proliferation in the Fetal Mouse Testis

“…In addition, activin A dosage affects growth of the fetal murine epididymis between E15.5 and E19.5 [13], and has the capacity to influence Sertoli cell proliferation and cord expansion in the mouse [14]. Our previous preliminary results [15] indicated that activin contributed to the suppression of germ cell numbers in the fetal testis, but the timing and mechanism by which this occurred were unknown.…”

Inhibin, activin, follistatin and FSH serum levels and testicular production are highly modulated during the first spermatogenic wave in mice

“…These observations suggest a dual role of activin regulation on gonocyte development, where a reduction in local activin concentration is required for gonocytes to exit from their state of G1 arrest, while subsequent elevation in activin levels suggests a role in promoting gonocyte proliferation. The role of activin as an inducer of mitotic arrest in gonocytes is evident in the elevated gonocyte numbers in testes of newborn mice lacking the b A subunit (Inhba K/K ; Loveland et al 2005). Subsequently, the role of activin as a mitogen is reflected in a study of 3-day-old rat testis fragment cultures, which showed that increased activin levels induced the proliferation of gonocytes (Meehan et al 2000).…”

Fsh Stimulates Spermatogonial Proliferation and Differentiation in Zebrafish via Igf3

“…line-derived neurotrophic factor, GDNF, (5)(6)(7); activin A and bone morphogenetic protein 4, BMP4, (8,9)], Leydig or peritubular myoid cells [colony-stimulating factor (CSF) 1, CSF1 (10 -11)], contribute to the niche homeostasis, and influence the balance between SSC self-renewal and differentiation (4). It is possible that yet unknown factors participate in regulating germ cell proliferation/ differentiation or that known factors exert yet unknown functions in the testis.…”