Glial cell line-derived neurotrophic factor maintains a POZ-itive influence on stem cells

Abstract

In adult males, germ-line stem cells have the remarkable ability to both self-renew and differentiate, ensuring that a continuous population of mature spermatozoa is produced throughout the lifetime of the animal. This balance between self-renewal and differentiation is thought to depend on the proper cellular environment, or stem cell “niche,” that provides the appropriate signals at the right time for these processes. One growth factor shown to be essential for mammalian spermatogonial stem cell (SSC) self-renewal is the glial cell line-derived neurotrophic factor (GDNF) (1). GDNF signals through a receptor complex containing the RET receptor tyrosine kinase and the GDNF family receptor α1 (GFRα1). Gdnf −/− mouse testes transplanted into WT recipients exhibit a rapid and dramatic loss of SSCs, resulting in testes that contain only the supporting Sertoli cells (2). The development of a culture method and transplantation assay for mouse SSCs has shown that when GDNF is removed from the culture media, the agametic recipient testes into which these cells are transplanted fail to be repopulated, indicating a loss of SSCs (3). Clearly, GDNF is necessary for SSC maintenance, but until now the downstream target genes activated by GDNF and demonstrated as important for SSC self-renewal were unknown. The work of Oatley et al. (4) in a recent issue of PNAS identifies genes regulated by GDNF by using the SSC culture system and microarray analysis. One of these genes, Bcl6b, is a member of the POZ (poxvirus and zinc finger) family of transcriptional repressors that also includes Plzf, previously shown to be required for SSC maintenance (5, 6). These results underscore the importance of the niche in the mammalian testis and extend its molecular characterization by identifying downstream targets of GDNF.