The Role of Retinoic Acid (RA) in Spermatogonial Differentiation

Retinoic acid (RA) directs the sequential, but distinct, programs of spermatogonial differentiation and meiotic differentiation that are both essential for the generation of functional spermatozoa. These processes are functionally and temporally decoupled, as they occur in distinct cell types that arise over a week apart, both in the neonatal and adult testis. However, our understanding is limited in terms of what cellular and molecular changes occur downstream of RA exposure that prepare differentiating spermatogonia for meiotic initiation. In this review, we describe the process of spermatogonial differentiation and summarize the current state of knowledge regarding RA signaling in spermatogonia

THE ROLE OF RETINOIC ACID IN DIRECTING INITIATION OF SPERMATOGENESIS IN THE MOUSE

The basic tenets of gametogenesis are conserved among metazoans. After lineage commitment, germ cells proliferate, complete meiosis, and then differentiate into gametes capable of fertilization. In the mouse, spermatogenesis begins at approximately postnatal day (P) 3-4, as prospermatogonia transition into distinct populations of spermatogonia. Some prospermatogonia become spermatogonial stem cells (SSCs) that provide a consistent source of gametes throughout the male reproductive lifespan. The remaining prospermatogonia proliferate and directly differentiate (without going through an SSC stage) in response to retinoic acid (RA) to eventually enter meiosis at P10. The pathways and cellular mechanisms that direct this critical cell fate decision are poorly defined. This dissertation summarizes the results of an examination of the cellular and molecular changes that occur downstream of RA signaling that direct prospermatogonia at P0-2 to transition to differentiating spermatogonia at P3-4. The results support a novel mechanism by which RA directs spermatogonial differentiation during spermatogenesis

The Role of Retinoic Acid (RA) in Spermatogonial Differentiation

Retinoic acid (RA) directs the sequential, but distinct, programs of spermatogonial differentiation and meiotic differentiation that are both essential for the generation of functional spermatozoa. These processes are functionally and temporally decoupled, as they occur in distinct cell types that arise over a week apart, both in the neonatal and adult testis. However, our understanding is limited in terms of what cellular and molecular changes occur downstream of RA exposure that prepare differentiating spermatogonia for meiotic initiation. In this review, we describe the process of spermatogonial differentiation and summarize the current state of knowledge regarding RA signaling in spermatogonia

Mammalian target of rapamycin complex 1 (mTORC1) Is required for mouse spermatogonial differentiation in vivo

AbstractSpermatogonial stem cells (SSCs) must balance self-renewal with production of transit-amplifying progenitors that differentiate in response to retinoic acid (RA) before entering meiosis. This self-renewal vs. differentiation spermatogonial fate decision is critical for maintaining tissue homeostasis, as imbalances cause spermatogenesis defects that can lead to human testicular cancer or infertility. A great deal of effort has been exerted to understand how the SSC population is maintained. In contrast, little is known about the essential program of differentiation initiated by retinoic acid (RA) that precedes meiosis, and the pathways and proteins involved are poorly defined. We recently reported a novel role for RA in stimulating the PI3/AKT/mTOR kinase signaling pathway to activate translation of repressed mRNAs such as Kit. Here, we examined the requirement for mTOR complex 1 (mTORC1) in mediating the RA signal to direct spermatogonial differentiation in the neonatal testis. We found that in vivo inhibition of mTORC1 by rapamycin blocked spermatogonial differentiation, which led to an accumulation of undifferentiated spermatogonia. In addition, rapamycin also blocked the RA-induced translational activation of mRNAs encoding KIT, SOHLH1, and SOHLH2 without affecting expression of STRA8. These findings highlight dual roles for RA in germ cell development – transcriptional activation of genes, and kinase signaling to stimulate translation of repressed messages required for spermatogonial differentiation