Notch signaling induces retinal stem-like properties in perinatal neural retina progenitors and promotes symmetric divisions in adult retinal stem cells.
Understanding the mechanisms regulating retinal stem cell (RSC) activity is fundamental for future stem cell-based therapeutic purposes. By combining gain and loss of function approaches, we addressed whether Notch signaling may play a selective role in retinal stem versus retinal progenitor cells in both developing and adult eyes. Inhibition of either Notch or fibroblast growth factor signaling reduced proliferation of retinal stem and retinal progenitor cells, and inhibited RSC self-renewal. Conversely, exogenous Delta-like 3 and direct intrinsic Notch activation stimulated expansionary symmetric divisions in adult RSCs with the concomitant upregulation of Hes5. Knocking down Hes5 expression specifically decreased the numbers, but not the diameters, of adult RSC primary spheres, indicating that HES5 is the downstream effector of Notch receptor in controlling adult RSC proliferation. In addition, constitutive Notch activation induced retinal stem-like asymmetric self-renewal properties, with no expansion (no symmetrical division) in perinatal neural retina progenitor cells. These findings highlight central roles of Notch signaling activity in regulating the modes of division of retinal stem and retinal progenitor cells.
Department of Molecular Genetics, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , Toronto, Canada .
Laurent
L
Balenci
Derek
D
van der Kooy
D053687:Adult Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000235:genetics*; D005260:Female; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction
D051792:Basic Helix-Loop-Helix Proteins; D005346:Fibroblast Growth Factors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D012097:Repressor Proteins; C511877:Dll3 protein, mouse; C489685:Hes5 protein, mouse