Mechanism of meiosis initiation in spermatogonia

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The mechanism underlying meiosis initiation has yet to be clarified. We have shown that there is a checkpoint of meiosis initiation in the 7^<th> generation of spermatogonia in newt testis and presented a hypothesis that meiosis initiation is regulated by the concentration ratio of FSH and prolactin. It was thought that meiosis initiation requires Sertoli cells, upon stimulation by FSH, produce some factor(s) that circumvent apoptosis and act on spermatogonia.Hence we screened cDNA microarray derived from newt testis and identified neuregulin (NRG) as one of the FSH-upregulated clones. It was revealed that Ig-type NRG is expressed in Sertoli cells, while CRD-type mRNA is expressed in both Sertoli and germ cells. FSH stimulates the expression of Ig-type mRNA highly, but not that of CRD-type. When recombinant protein of the EGF-like domain which is a functional domain of NRG is added to organ culture of the testis, it stimulated the spermatogonial proliferation.Then we found that NRG mRNA is expressed in mouse testis; NRG1 mRNA level expressed in Sertoli cells decreases as development proceeds, while NRG 3 mRNA level expressed both in Sertoli and germ cells increases. Recombinant proteins of NRG1 and 3 were added to organ culture of testis from 6dpp when only A-type spermatogonia are present, resulting in promotion of spermatogonial proliferation and expression of SPO11 mRNA that is specific to primary spermatocytes. FSH stimulated the expression of NRGs mRNA. These results indicate that NRGs play a pivotal role in meiosis initiation as important factors to act on spermatogonia.