title: Beta1 integrins activate a MAPK signalling pathway in neural stem cells that contributes to their maintenance.
abstract: The emerging evidence that stem cells develop in specialised niches highlights the potential role of environmental factors in their regulation. Here we examine the role of beta1 integrin/extracellular matrix interactions in neural stem cells. We find high levels of beta1 integrin expression in the stem-cell containing regions of the embryonic CNS, with associated expression of the laminin alpha2 chain. Expression levels of laminin alpha2 are reduced in the postnatal CNS, but a population of cells expressing high levels of beta1 remains. Using neurospheres - aggregate cultures, derived from single stem cells, that have a three-dimensional architecture that results in the localisation of the stem cell population around the edge of the sphere - we show directly that beta1 integrins are expressed at high levels on neural stem cells and can be used for their selection. MAPK, but not PI3K, signalling is required for neural stem cell maintenance, as assessed by neurosphere formation, and inhibition or genetic ablation of beta1 integrin using cre/lox technology reduces the level of MAPK activity. We conclude that integrins are therefore an important part of the signalling mechanisms that control neural stem cell behaviour in specific areas of the CNS.
authors.affiliation: Department of Medical Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Lia S
authors.initials: LS
authors.lastname: Campos
authors.forename: Dino P
authors.initials: DP
authors.lastname: Leone
authors.forename: Joao B
authors.initials: JB
authors.lastname: Relvas
authors.forename: Cord
authors.initials: C
authors.lastname: Brakebusch
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: Charles
authors.initials: C
authors.lastname: ffrench-Constant
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D018929:Cell Culture Techniques / Q000379:methods; D002469:Cell Separation; D002478:Cells, Cultured; D004396:Coloring Agents / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis / Q000378:metabolism; D005434:Flow Cytometry; D007150:Immunohistochemistry; D019012:Integrin beta1 / Q000502:physiology*; D007797:Laminin / Q000096:biosynthesis / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors
chemical_list: D004396:Coloring Agents; D005353:Fibronectins; D019012:Integrin beta1; D007797:Laminin; C102645:laminin alpha 2; D001973:Bromodeoxyuridine