Spermatogonial stem cell fate

The Matunis lab studies stem cells that sustain spermatogenesis in the fruit fly Drosophila melanogaster. Stem cells can replicate indefinitely, yet also give rise to more specialized tissue cells in response to appropriate environmental cues. Because of their unique regenerative properties, stem cells are the focus of much research. However, because these cells are usually rare, and reside in complex environments, little is known about how they behave in vivo. The researchers' goal is, therefore, to use genetics to identify the environmental cues that regulate stem cells in the Drosophila testis.

In most cases, stem cells cannot be distinguished from their progeny, making it difficult or impossible to determine their location within the tissues they regenerate. However, germ line stem cells (gscs) in the Drosophila testis can be identified directly, because they are attached to a small cluster of somatic cells called the hub. When a germ line stem cell divides, one daughter remains attached to the hub and retains a stem cell fate. In contrast, the other daughter (called a spermatoblast) is displaced away from the hub and differentiates into a bundle of sperm (see diagram). This suggests that cells nearest the hub receive signals needed to maintain stem cell fate, while spermatoblasts that leave this specialized local environment, or niche, lose their stem cell character and differentiate. This type of mechanism is hypothesized to operate in many stem cell systems, but it has been extremely difficult to prove.

The Matunis lab is searching for molecules that regulate stem cells by genetically removing candidate signaling molecules from this tissue and looking for a corresponding change in the number of stem cells. Using this approach, the scientists have found that the Jak-Stat signaling pathway is required to maintain gscs. In this highly conserved pathway, extracellular ligands activate receptor-associated cytoplasmic protein tyrosine kinases (Janus, or Jak kinases), which in turn activate transcription factors in the Signal Transducer and Activator of Transcription (STAT) family. A ligand that activates the Jak-Stat pathway during spermatogenesis has been identified, and its expression is localized to the hub. Overproducing this ligand in the testis leads to a dramatic increase in stem cell numbers (see figure). This suggests that Jak-Stat signaling instructs stem cell fate, rather than maintaining cell viability. Together, these data support the hypothesis that the hub defines a stem cell niche, wherein localized activation of the Jak-Stat pathway instructs the self-renewal of nearby stem cells. The researchers are currently asking if the Jak-Stat pathway is activated directly in the gscs, or in nearby somatic cells.