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.1,2 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.3 Knockout of Shp2 in the embryonic precursor germ cells (gonocytes) demonstrated that this protein is essential for the production of undifferentiated spermatogonia.4 However, although both Shp2 inhibition or global knockout suggested a role in adult germ cells,5 its specific function in this cell population has yet to be established.
In Asian Journal of Andrology, Li et al.6 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.7 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.6 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.6 and from previous studies5 suggest that permanent infertility could be a side effect of therapies being developed to inhibit SHP2.8
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
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