What are the signals regulating stem cell fate?
A major goal in stem cell biology is to understand how the balance between stem cell renewal and differentiation is controlled. Signals from neighboring cells are key regulators of stem cells. However, identifying these signals has proven very difficult in many systems, since the precise location of stem cells is usually unknown. However, by studying stem cells that sustain spermatogenesis in the fruit fly Drosophila melanogaster, we have begun to get a much clearer
idea of stem cell regulation. In this tissue, germ line stem cells (GSCs,) attach to a cluster of non-dividing somatic cells called the hub. When a GSC divides, its daughter is pushed away from the hub and differentiates into a gonialblast (GB). Somatic stem cells called Cyst Progenitor Cells, are also anchored at the hub, and produce cyst cells that form an envelope around each GB to support its development. We can readily see all of the cells comprising this stem cell niche by confocal microscopy.
Local signaling controls stem cell renewal:
How do GSC divisions produce two cells with such different fates? The GSC could receive a signal from the hub that allows it to remain a stem cell, while the daughter displaced away from the hub loses the signal, and differentiates. This is thought to happen in many stem cell systems, but has been extremely difficult to prove. However, we have found that this is how stem cells are renewed in the fly testis, and we have identified the key regulatory signal. The hub secretes a ligand (called Unpaired), that activates the Janus kinase-Signal transducer and activator of transcription (Jak-Stat) signaling pathway within GSCs. Activation of Jak-Stat within GSCs ensures that they remain stem cells; GB do not receive enough Upd to activate Jak-Stat, and instead differentiate.
Currently we are using genetic and genomic approaches to identify targets of Stat within GSCs, since these genes molecularly define the GSC fate. We are also determining if the hub directly activates Stat in somatic stem cells, or if a different mechanism is operating to ensure their renewal, since little is known of how two stem cell populations are regulated within one niche. We are also asking how the stem cell niche is established during development.
Finally, we have recently found that spermatogonia that have begun to differentiate can reverse their path and de-differentiate to become GSCs. We are very interested in understanding the mechanisms controlling de-differentiation.
Publications:
Buszczak M, Paterno S, Lighthouse D, Bachman J, Plank J, Owen S, Skora A, Nystul T, Ohlstein B, Allen A, Wilhelm J, Murphy T, Levis B,
Matunis E, Srivali N, Hoskins R, Spradling A. 2007. The Carnegie protein trap library: a versatile tool for Drosophila developmental studies. Genetics. 175:1501-1531. PMID: 17194782
Terry, N.A, N. Tulina, E. Matunis, and S. DiNardo. 2006. Novel regulators revealed by profiling Drosophila testis stem cells within their niche. Dev. Biol. 294:246-57. PMID: 16616121
Wawersik, M., A. Milutinovich, E. Matunis, B. Williams, and M. Van Doren. 2005. Somatic control of germline sexual differentiation is mediated by the JAK/STAT pathway. Nature 436:563-567. PMID: 16049490
Brawley, C and E. Matunis. 2004. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 304:1331-1334. PMID: 15143218
Watnick, T.J., Y. Jin, E. Matunis, M.J. Kernan, and C. Montell. 2003. A flagellar polycystin-2 homolog required for male fertility in Drosophila. Current Biology 13: 2179-2184. PMID: 14680634
Wallenfang, M. and E. Matunis. 2003. Orienting Stem cells. Science 310: 1490-1491. PMID: 12970553
Tulina, N., and E. Matunis. 2001. Control of Stem cell self-renewal in Drosophila spermatogenesis by Jak-STAT signaling. Science 294: 2546-2549. PMID: 1175257
