|Ahead of print publication
Teasing apart the multiple roles of Shp2 (Ptpn11) in spermatogenesis
Geoffrey J Maher, Anne Goriely
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
|Date of Submission||20-May-2019|
|Date of Acceptance||28-May-2019|
|Date of Web Publication||30-Jul-2019|
Geoffrey J Maher,
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS
Source of Support: None, Conflict of Interest: None
Article in PDF
Geoffrey J Maher
Current Address: ICTEM Building, Hammersmith Campus, Imperial College
London, Du Cane Road, London, W12 0NN, UK.
Male germ cells are the only adult cells to undergo the intricate process of meiosis, which is preceded by the complex molecular transition from mitotic spermatogonia to spermatocytes. Recent single-cell transcriptomic studies have shown that this transition involves differential expression of thousands of genes., Pinpointing the specific roles played by key regulators of this process is crucial to further our understanding of male fertility and, in the long-term, to support the development of infertility therapy and in vitro spermatogenesis.
The tyrosine phosphatase Shp2 (encoded by the gene Ptpn11) has previously been shown to have multiple roles during mouse spermatogenesis: loss of Shp2 expression in Sertoli cells disrupts the integrity of the blood–testis barrier and also results in a reduction of spermatogonia number and increased expression of differentiation-promoting factors. Knockout of Shp2 in the embryonic precursor germ cells (gonocytes) demonstrated that this protein is essential for the production of undifferentiated spermatogonia. However, although both Shp2 inhibition or global knockout suggested a role in adult germ cells, its specific function in this cell population has yet to be established.
In Asian Journal of Andrology, Li et al. address this aspect by investigating the role of Shp2 in the postnatal germ cells using a Stra8-Cre driver strain. They show that this germ cell-specific knockout causes increased differentiation of spermatogonia and reduced numbers of meiotic cells. Abnormal expression of numerous genes/proteins associated with meiotic recombination and synapsis was also identified, consistent with a role for Shp2 in the transition from spermatogonia to spermatocytes.
In humans, a role for SHP2 in spermatogenesis has previously been inferred from genetic studies which revealed that pathogenic gain-of-function mutations in PTPN11 are associated with conferring a “selfish” selective advantage to spermatogonia. This results in the formation of mutant clones that spread within seminiferous tubules with age. If passed on to progeny, these mutations cause the developmental disorder Noonan syndrome. Given this, it would be interesting to assess the effects of Ptpn11 gain-of-function mutations in murine adult spermatogonia – which may provide further clues on the role of SHP2 in spermatogenesis and human disease.
Although Li et al. propose that activation of SHP2 could be a potential target for the treatment of male infertility, given that PTPN11 is a known oncogene, implementing such an approach could carry some risks. On the other hand, data from Li et al. and from previous studies suggest that permanent infertility could be a side effect of therapies being developed to inhibit SHP2.
Delineating the role of Ptpn11/Shp2 in adult spermatogenesis provides a valuable insight into the multifaceted functions of this key disease gene.
| Competing Interests|| |
Both authors declare no competing interests.
| References|| |
Guo J, Grow EJ, Mlcochova H, Maher GJ, Lindskog C, et al
. The adult human testis transcriptional cell atlas. Cell Res
2018; 28: 1141–57.
Hermann BP, Cheng K, Singh A, Roa-De La Cruz L, Mutoji KN, et al. The mammalian spermatogenesis single-cell transcriptome, from spermatogonial stem cells to spermatids. Cell Rep 2018; 25: 1650–67.
Hu X, Tang Z, Li Y, Liu W, Zhang S, et al
. Deletion of the tyrosine phosphatase Shp2 in Sertoli cells causes infertility in mice. Sci Rep
2015; 5: 12982.
Puri P, Phillips BT, Suzuki H, Orwig KE, Rajkovic A, et al
. The transition from stem cell to progenitor spermatogonia and male fertility requires the SHP2 protein tyrosine phosphatase. Stem Cells
2014; 32: 741–53.
Puri P, Walker WH. The tyrosine phosphatase SHP2 regulates Sertoli cell junction complexes. Biol Reprod
2013; 88: 59.
Li Y, Liu WS, Yi J, Kong SB, Ding JC, et al
. The role of tyrosine phosphatase Shp2 in spermatogonial differentiation and spermatocyte meiosis. Asian J Androl
2019; Doi: 10.4103/aja.aja_49_19. [Epub ahead of print].
Maher GJ, Ralph HK, Ding Z, Koelling N, Mlcochova H, et al
. Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes. Genome Res
2018; 28: 1779–90.
Frankson R, Yu ZH, Bai Y, Li Q, Zhang RY, et al
. Therapeutic targeting of oncogenic tyrosine phosphatases. Cancer Res
2017; 77: 5701–5.