Analysis of Tenascin-C (TN-C) knockout mice revealed novel roles for this extracellular matrix (ECM) protein in regulation of the developmental programme of oligodendrocyte precursor cells (OPCs), their maturation into myelinating oligodendrocytes and sensitivity to growth factors. A major component of the ECM of developing nervous tissue, TN-C was expressed in zones of proliferation, migration and morphogenesis. Examination of TN-C knockout mice showed roles for TN-C in control of OPC proliferation and migration towards zones of myelination [E. Garcion et al. (2001) Development, 128, 2485–2496]. Extending our studies of TN-C effects on OPC development we found that OPCs can endogenously express TN-C protein. This expression covered the whole range of possible TN-C isoforms and could be strongly up-regulated by leukaemia inhibitory factor and ciliary neurotrophic factor, cytokines known to modulate OPC proliferation and survival. Comparative analysis of TN-C knockout OPCs with wild-type OPCs reveals an accelerated rate of maturation in the absence of TN-C, with earlier morphological differentiation and precocious expression of myelin basic protein. TN-C knockout OPCs plated on poly-lysine displayed higher levels of apoptosis than wild-type OPCs and there was also an earlier loss of responsiveness to the protective effects of platelet-derived growth factor (PDGF), indicating that TN-C has anti-apoptotic effects that may be associated with PDGF signalling. The existence of mechanisms to compensate for the absence of TN-C in the knockout is indicated by the development of oligodendrocytes derived from TN-C knockout neurospheres. These were present in equivalent proportions to those found in wild-type neurospheres but displayed enhanced myelin membrane formation.