Faculty & Research
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Research Topic: Signals Regulating Stem Cell Self-renewal
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.
Sheng XR, Matunis EL.
Live imaging of the Drosophila spermatogonial stem cell niche reveals novel mechanisms regulating germline stem cell output.
Development 16:3367-3376.PubMed Reference
de Cuevas M, Matunis EL.
The stem cell niche: Lessons from the Drosophila testis.
Development 14:2861-2969.PubMed Reference
Cherry CM, Matunis EL.
Epigenetic regulation of stem cell maintenance in the Drosophila testis via the nucleosome remodeling factor NURF.
Cell Stem Cell 6:557-567.PubMed Reference
Issigonis M, Tulina N, de Cuevas M, Brawley C, Sandler L, Matunis E.
JAK-STAT signal inhibition regulates competition within the Drosophila testis stem cell niche.
Science 326:153-6.PubMed Reference
Sheng XR, Brawley CM, Matunis EL.
2009. Dedifferentiating spermatogonia outcompete somatic stem cells for niche occupancy in the Drosophila testis.
Cell Stem Cell 5:191-203.PubMed Reference
Sheng XR, Posenau T, Gumulak-Smith JJ, Matunis EL
, Van Doren M, Wawersik M. 2009. Jak-STAT regulation of male germline stem cell establishment during Drosophila embryogenesis.
Dev. Biol. 334:335-344.PubMed Reference
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. EL
, Srivali N, Hoskins R, Spradling A.
The Carnegie protein trap library: a versatile tool for Drosophila developmental studies.
Genetics 175:1501-1531.PubMed Reference
Terry NA, Tulina N, Matunis EL., DiNardo S. 2006. Novel regulators revealed by profiling Drosophila testis stem cells within their niche. Dev. Biol. 294:246-257.
Wawersik M, Milutinovich A, Matunis EL,
Williams B, Van Doren M.
Somatic control of germline sexual differentiation is mediated by the JAK/STAT pathway. Nature 436:563-567.PubMed Reference
Brawley C, Matunis EL.
2004. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo.
Science 304:1331-1334.PubMed Reference
Tulina N, Matunis EL.
Control of Stem cell self-renewal in Drosophila
spermatogenesis by Jak-STAT signaling.
Science 294: 2546-2549.PubMed Reference