Niche-associated activation of rac promotes the asymmetric division of Drosophila female germline stem cells.
BACKGROUND
Drosophila female germline stem cells (GSCs) reside adjacent to a cellular niche that secretes Bone Morphogenetic Protein (BMP) ligands and anchors the GSCs through adherens junctions. The GSCs divide asymmetrically such that one daughter remains in the niche as a GSC, while the other is born away from the niche and differentiates. However, given that the BMP signal can be diffusible, it remains unclear how a local extracellular asymmetry is sufficient to result in a robust pattern of asymmetric division.


RESULTS
Here we show that GSCs are polarized with respect to the cellular niche. We first use a modified biosensor to demonstrate that the small GTPase Rac is asymmetrically activated within the GSC at the niche-GSC interface. Experiments using loss-of-function and gain-of-function mutations in Rac indicate that asymmetric Rac activity both localizes the microtubule binding protein Apc2 to orient one GSC centrosome at the niche-GSC interface during interphase and activates the Jun N-terminal kinase pathway to increase the ability of the GSC to respond to BMP ligands. Other processes act in concert with each function of Rac. Specifically, we demonstrate that the GSC cell cycle arrests at prometaphase if centrosomes are misoriented.


CONCLUSIONS
Thus, the GSCs, an adult stem cell present in a cellular niche, have a niche-associated polarity that couples control of the division plane with increased response to an extracellular maintenance signal. Other processes work in parallel with the Rac-mediated polarity to ensure a robust pattern of asymmetric division. We suggest that all adult stem cells likely employ multiple, independently acting mechanisms to ensure asymmetric division to maintain tissue homeostasis.
Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America.
Wen
W
Lu
M Olivia
MO
Casanueva
Anthony P
AP
Mahowald
Mihoko
M
Kato
David
D
Lauterbach
Edwin L
EL
Ferguson
D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D019521:Body Patterning; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D016764:Cell Polarity; D018385:Centrosome / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism; D007399:Interphase; D008024:Ligands; D020935:MAP Kinase Signaling System; D008297:Male; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013737:Testis / Q000166:cytology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C467323:APC2 protein, Drosophila; D029721:Drosophila Proteins; D008024:Ligands; C090146:Rac1 protein, Drosophila; D025521:Tumor Suppressor Proteins; D020744:rac GTP-Binding Proteins