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Asian J Androl. 2019 Jun 14. doi: 10.4103/aja.aja_49_19. [Epub ahead of print]

The role of tyrosine phosphatase Shp2 in spermatogonial differentiation and spermatocyte meiosis.

Author information

1
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen 361005, China.
2
Fujian Provincial Key Laboratory of Reproductive Health Research, Medical College of Xiamen University, Xiamen 361005, China.
3
Department of Pathology, Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093, USA.
4
Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and Medical School of Nanjing University, National Resource Center for Mutant Mice, Nanjing 210061, China.
5
Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen 361005, China.

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.

KEYWORDS:

cell differentiation; gene expression; spermatogenesis; transgenic mouse

PMID:
31210146
DOI:
10.4103/aja.aja_49_19
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