PMID- 20451518 OWN - NLM STAT- MEDLINE DCOM- 20101020 LR - 20101118 IS - 1090-2430 (Electronic) IS - 0014-4886 (Linking) VI - 225 IP - 1 DP - 2010 Sep TI - Analysis of combinatorial variability reveals selective accumulation of the fibronectin type III domains B and D of tenascin-C in injured brain. PG - 60-73 LID - 10.1016/j.expneurol.2010.04.019 [doi] AB - Tenascin-C (Tnc) is a multimodular extracellular matrix glycoprotein that is markedly upregulated in CNS injuries where it is primarily secreted by reactive astrocytes. Different Tnc isoforms can be generated by the insertion of variable combinations of one to seven (in rats) alternatively spliced distinct fibronectin type III (FnIII) domains to the smallest variant. Each spliced FnIII repeat mediates specific actions on neurite outgrowth, neuron migration or adhesion. Hence, different Tnc isoforms might differentially influence CNS repair. We explored the expression pattern of Tnc variants after cortical lesions and after treatment of astrocytes with various cytokines. Using RT-PCR, we observed a strong upregulation of Tnc transcripts containing the spliced FnIII domains B or D in injured tissue at 2-4 days post-lesion (dpl). Looking at specific combinations, we showed a dramatic increase of Tnc isoforms harboring the neurite outgrowth-promoting BD repeat with both the B and D domains being adjacent to each other. Isoforms containing only the axon growth-stimulating spliced domain D were also dramatically enhanced after injury. Injury-induced increase of Tnc proteins comprising the domain D was confirmed by Western Blotting and immunostaining of cortical lesions. In contrast, the FnIII modules C and AD1 were weakly modulated after injury. The growth cone repulsive A1A2A4 domains were poorly expressed in normal and injured tissue but the smallest isoform, which is also repellant, was highly expressed after injury. Expression of the shortest Tnc isoform and of variants containing B, D or BD, was strongly upregulated in cultured astrocytes after TGFbeta1 treatment, suggesting that TGFbeta1 could mediate, at least in part, the injury-induced upregulation of these isoforms. We identified complex injury-induced differential regulations of Tnc isoforms that may well influence axonal regeneration and repair processes in the damaged CNS. CI - Copyright 2010. Published by Elsevier Inc. FAU - Dobbertin, Alexandre AU - Dobbertin A AD - Department of Cell Morphology and Molecular Neurobiology, Ruhr University of Bochum, 44780 Bochum, Germany. FAU - Czvitkovich, Stefan AU - Czvitkovich S FAU - Theocharidis, Ursula AU - Theocharidis U FAU - Garwood, Jeremy AU - Garwood J FAU - Andrews, Melissa R AU - Andrews MR FAU - Properzi, Francesca AU - Properzi F FAU - Lin, Rachel AU - Lin R FAU - Fawcett, James W AU - Fawcett JW FAU - Faissner, Andreas AU - Faissner A LA - eng GR - Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20100505 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Cell Adhesion Molecules, Neuronal) RN - 0 (Contactins) RN - 0 (Fibronectins) RN - 0 (Protein Isoforms) RN - 0 (Tenascin) SB - IM MH - Alternative Splicing/genetics MH - Animals MH - Animals, Newborn MH - Astrocytes/*metabolism/pathology MH - Brain Injuries/genetics/*metabolism/pathology MH - Cell Adhesion Molecules, Neuronal/biosynthesis/metabolism/physiology MH - Cells, Cultured MH - Contactins MH - Disease Models, Animal MH - Female MH - Fibronectins/genetics/*metabolism/physiology MH - Nerve Regeneration/physiology MH - Protein Isoforms/biosynthesis/chemistry/physiology MH - Protein Structure, Tertiary/genetics/physiology MH - Rats MH - Rats, Sprague-Dawley MH - Tenascin/genetics/*metabolism/physiology EDAT- 2010/05/11 06:00 MHDA- 2010/10/21 06:00 CRDT- 2010/05/11 06:00 PHST- 2009/12/22 00:00 [received] PHST- 2010/04/23 00:00 [revised] PHST- 2010/04/30 00:00 [accepted] PHST- 2010/05/11 06:00 [entrez] PHST- 2010/05/11 06:00 [pubmed] PHST- 2010/10/21 06:00 [medline] AID - S0014-4886(10)00156-1 [pii] AID - 10.1016/j.expneurol.2010.04.019 [doi] PST - ppublish SO - Exp Neurol. 2010 Sep;225(1):60-73. doi: 10.1016/j.expneurol.2010.04.019. Epub 2010 May 5.