Tissue inhibitor of metalloproteinase-2 (TIMP-2) expression is regulated by multiple neural differentiation signals.
Neuronal differentiation requires exquisitely timed cell cycle arrest for progenitors to acquire an appropriate neuronal cell fate and is achieved by communication between soluble signals, such as growth factors and extracellular matrix molecules. Here we report that the expression of TIMP-2, a matrix metalloproteinase inhibitor, is up-regulated by signals that control proliferation (bFGF and EGF) and differentiation (retinoic acid and NGF) in neural progenitor and neuroblastoma cell lines. TIMP-2 expression coincides with the appearance of neurofilament-positive neurons, indicating that TIMP-2 may play a role in neurogenesis. The up-regulation of TIMP-2 expression by proliferate signals suggests a role in the transition from proliferation to neuronal differentiation. Live labeling experiments demonstrate TIMP-2 expression only on alpha(3) integrin-positive cells. Thus, TIMP-2 function may be mediated via interaction with integrin receptor(s). We propose that TIMP-2 represents a component of the neurogenic signaling cascade induced by mitogenic stimuli that may withdraw progenitor cells from the cell cycle permitting their terminal neuronal differentiation.
Jaworski
Diane M
DM
Department of Anatomy & Neurobiology, University of Vermont College of Medicine, Burlington, Vermont, USA. diane.jaworski@uvm.edu
Pérez-Martínez
Leonor
L
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D044967:Serum / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D006133:Growth Substances; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2