The transcriptional corepressor TPA-inducible sequence 7 regulates adult axon growth through cellular retinoic acid binding protein II expression.

TPA-inducible sequence 7 (TIS7) expression is regulated in epithelial cells and acts as a transcriptional corepressor. Using a TIS7 knock-out mouse we demonstrated that TIS7 is involved in the process of muscle regeneration. In this study, we analysed the role of TIS7 in axon regeneration, applying primary neurone cultures derived from adult dorsal root ganglia (DRGs) of TIS7+/+ and TIS7-/- mice. TIS7-/- DRG neurones exhibited a significant decrease in axon initiation and maximal axon extension. In contrast, nerve growth factor-induced axon initiation and branching were significantly enhanced in cultures obtained from TIS7-/- DRGs when compared with wildtype ganglia, suggesting an inhibitory effect of TIS7 on nerve growth factor-stimulated axon growth. TIS7 overexpression in TIS7-/- DRG neurones caused their morphological appearance to revert back to the wildtype phenotype. Furthermore, the expression of cellular retinoic acid binding protein II (CRABP II), previously identified by us as a TIS7 target gene, was up-regulated in adult DRG sensory neurones from TIS7-/- mice. Overexpression of CRABP II in TIS7+/+ neurones strongly increased the number of branch points, making them morphologically similar to TIS7-/- neurones. Based on these results we propose that TIS7 inhibits CRABP II expression during axonal regeneration, thereby modulating retinoic acid signalling. Hence, neurite initiation and branching are regulated by a negative feedback mechanism involving TIS7 and CRABP II.