Dissecting integrin-dependent regulation of neural stem cell proliferation in the adult brain.
Controlling neural stem and progenitor cell (NSPC) proliferation is critical to maintain neurogenesis in the mammalian brain throughout life. However, it remains poorly understood how niche-derived cues such as β1-integrin-mediated signaling are translated into NSPC-intrinsic molecular changes to regulate NSPC activity. Here we show that genetic deletion of integrin-linked kinase (ILK) increases NSPC proliferation through PINCH1/2-dependent enhancement of c-Jun N-terminal protein kinase activity in both neurogenic regions of the adult mouse brain. This effect downstream of ILK signaling is mediated through loss of Ras suppressor unit-1 (RSU-1), as virus-based reconstitution of RSU-1 expression rescued the ILK-dependent effects on NSPC proliferation. Thus, we here identified an intracellular signaling cascade linking extrinsic integrin-mediated signaling to NSPC proliferation and characterized a novel mechanism that regulates NSPC activity in the adult mammalian brain.
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland, and Brain Research Institute, Faculty of Medicine and Science, University of Zurich, 8057 Zurich, Switzerland.
Cristina
C
Porcheri
Ueli
U
Suter
Sebastian
S
Jessberger
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D055495:Neurogenesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055153:Stem Cell Niche; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099200:Scaffold Protein ILK
D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D000099200:Scaffold Protein ILK; C490232:Lims1 protein, mouse; C484099:Rsu1 protein, mouse
hippocampus; integrin; neurogenesis; niche; proliferation