Generation of an environmental niche for neural stem cell development by the extracellular matrix molecule tenascin C.
Stem cells in the embryonic mammalian CNS are initially responsive to fibroblast growth factor 2 (FGF2). They then undergo a developmental programme in which they acquire epidermal growth factor (EGF) responsiveness, switch from the production of neuronal to glial precursors and become localized in specialized germinal zones such as the subventricular zone (SVZ). Here we show that extracellular matrix molecules act as regulators of this programme. Tenascin C is highly expressed in the SVZ, and transgenic mice lacking tenascin C show delayed acquisition of the EGF receptor. This results from alterations in the response of the stem cells to the growth factors FGF2 and bone morphogenic protein 4 (BMP4), which normally promote and inhibit acquisition of the EGF receptor, respectively. Tenascin C-deficient mice also have altered numbers of CNS stem cells and these stem cells have an increased probability of generating neurones when grown in cell culture. We conclude that tenascin C contributes to the generation of a stem cell 'niche' within the SVZ, acting to orchestrate growth factor signalling so as to accelerate neural stem cell development.
Garcion
Emmanuel
E
Cambridge Centre for Brain Repair, and Department of Medical Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
Halilagic
Aida
A
Faissner
Andreas
A
ffrench-Constant
Charles
C
D000818:Animals; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002454:Cell Differentiation; D002455:Cell Division; D066246:ErbB Receptors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008858:Microscopy, Phase-Contrast; D008954:Models, Biological; D009420:Nervous System / Q000196:embryology*; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D019063:Tenascin / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D019063:Tenascin; D016222:Fibroblast Growth Factor 2; D066246:ErbB Receptors; D001973:Bromodeoxyuridine