is required for male germ cell development and spermatogonial stem cell maintenance.

The foundation of spermatogenesis and lifelong fertility is provided by spermatogonial stem cells (SSCs). SSCs divide asymmetrically to either replenish their numbers (self-renewal) or produce undifferentiated progenitors that proliferate before committing to differentiation. However, regulatory mechanisms governing SSC maintenance are poorly understood.

WNK1 is required during male pachynema to sustain fertility.

WNK1 is an important regulator in many physiological functions, yet its role in male reproduction is unexplored. In the male germline, WNK1 is upregulated in preleptotene spermatocytes indicating possible function(s) in spermatogenic meiosis. Indeed, deletion of in mid-pachytene spermatocytes using the mouse led to male sterility which resembled non-obstructive azoospermia in humans, where germ cells failed to complete spermatogenesis and produced no sperm.

Retinoic acid is dispensable for meiotic initiation but required for spermiogenesis in the mammalian testis.

Retinoic acid (RA) is the proposed mammalian 'meiosis inducing substance'. However, evidence for this role comes from studies in the fetal ovary, where germ cell differentiation and meiotic initiation are temporally inseparable. In the postnatal testis, these events are separated by more than 1 week.

Pharmacological Treatment of Neonatal and Juvenile Mice to Study Spermatogenesis.

The delivery, to newborn and juvenile mice, of drugs and other compounds that manipulate the physiology or cellular/molecular state -e.g., by activating or inhibiting signaling pathways) is a powerful, yet underutilized approach to studying spermatogenesis.

Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis†.

The foundation of mammalian spermatogenesis is provided by undifferentiated spermatogonia, which comprise of spermatogonial stem cells (SSCs) and transit-amplifying progenitors that differentiate in response to retinoic acid (RA) and are committed to enter meiosis. Our laboratory recently reported that the foundational populations of SSCs, undifferentiated progenitors, and differentiating spermatogonia are formed in the neonatal testis in part based on their differential responsiveness to RA. Here, we expand on those findings to define the extent to which RA responsiveness during steady-state spermatogenesis in the adult testis regulates the spermatogonial fate.

Modeling mammalian spermatogonial differentiation and meiotic initiation in vitro.

In mammalian testes, premeiotic spermatogonia respond to retinoic acid by completing an essential lengthy differentiation program before initiating meiosis. The molecular and cellular changes directing these developmental processes remain largely undefined. This wide gap in knowledge is due to two unresolved technical challenges: (1) lack of robust and reliable in vitro models to study differentiation and meiotic initiation; and (2) lack of methods to isolate large and pure populations of male germ cells at each stage of differentiation and at meiotic initiation.

Mammalian SWI/SNF chromatin remodeler is essential for reductional meiosis in males.

The mammalian SWI/SNF nucleosome remodeler is essential for spermatogenesis. Here, we identify a role for ARID2, a PBAF (Polybromo - Brg1 Associated Factor)-specific subunit, in meiotic division. Arid2 spermatocytes arrest at metaphase-I and are deficient in spindle assembly, kinetochore-associated Polo-like kinase1 (PLK1), and centromeric targeting of Histone H3 threonine3 phosphorylation (H3T3P) and Histone H2A threonine120 phosphorylation (H2AT120P).

The rapamycin analog Everolimus reversibly impairs male germ cell differentiation and fertility in the mouse†.

Sirolimus, also known as rapamycin, and its closely related rapamycin analog (rapalog) Everolimus inhibit "mammalian target of rapamycin complex 1" (mTORC1), whose activity is required for spermatogenesis. Everolimus is Food and Drug Administration approved for treating human patients to slow growth of aggressive cancers and preventing organ transplant rejection. Here, we test the hypothesis that rapalog inhibition of mTORC1 activity has a negative, but reversible, impact upon spermatogenesis.