ABSTRACT
The transition from spermatogonia to spermatocytes and the initiation of meiosis are key steps in spermatogenesis and are precisely regulated by a plethora of proteins. However, the underlying molecular mechanism remains largely unknown. Here, we report that Src homology domain tyrosine phosphatase 2 (Shp2; encoded by the protein tyrosine phosphatase, nonreceptor type 11 [Ptpn11] gene) is abundant in spermatogonia but markedly decreases in meiotic spermatocytes. Conditional knockout of Shp2 in spermatogonia in mice using stimulated by retinoic acid gene 8 (Stra8)-cre enhanced spermatogonial differentiation and disturbed the meiotic process. Depletion of Shp2 in spermatogonia caused many meiotic spermatocytes to die; moreover, the surviving spermatocytes reached the leptotene stage early at postnatal day 9 (PN9) and the pachytene stage at PN11-13. In preleptotene spermatocytes, Shp2 deletion disrupted the expression of meiotic genes, such as disrupted meiotic cDNA 1 (Dmc1), DNA repair recombinase rad51 (Rad51), and structural maintenance of chromosome 3 (Smc3), and these deficiencies interrupted spermatocyte meiosis. In GC-1 cells cultured in vitro, Shp2 knockdown suppressed the retinoic acid (RA)-induced phosphorylation of extracellular-regulated protein kinase (Erk) and protein kinase B (Akt/PKB) and the expression of target genes such as synaptonemal complex protein 3 (Sycp3) and Dmc1. Together, these data suggest that Shp2 plays a crucial role in spermatogenesis by governing the transition from spermatogonia to spermatocytes and by mediating meiotic progression through regulating gene transcription, thus providing a potential treatment target for male infertility.
Subject(s)
Animals , Male , Mice , Cell Cycle Proteins/genetics , Cell Line , Cell Survival , Chondroitin Sulfate Proteoglycans/genetics , Chromosomal Proteins, Non-Histone/genetics , Gene Expression Regulation , Gene Knockdown Techniques , Infertility, Male , Meiosis/genetics , Mice, Knockout , Mice, Transgenic , Phosphate-Binding Proteins/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Rad51 Recombinase/genetics , Real-Time Polymerase Chain Reaction , Spermatocytes/metabolism , Spermatogenesis/genetics , Spermatogonia/metabolismABSTRACT
This short article is dedicated to the 90th Anniversary of the School of Life Sciences at Zhejiang University, China. Immunotherapy of cancer is currently a hot topic in the biomedical field, and a re-search focus of my laboratory is on developing new and effective combinatorial immunotherapeutic strategies for liver cancer. Of note, my interest in immunotherapy of cancer stems from the training as an undergraduate student at Hangzhou University, China, almost 40 years ago.
