Targeted Effects

Abstract

Correct positioning of the presynaptic terminal of a motoneuron and the postsynaptic membrane of its target muscle are essential for the formation of an effective neuromuscular junction (NMJ). Compounds secreted from the presynaptic terminal such as agrin and acetylcholine (ACh) regulate clustering of ACh receptors (AChRs) in the muscle, and muscle-derived factors are thought to affect presynaptic terminal differentiation and function; however, the factors involved are unknown. Wnt proteins play a role in the development of the nervous system. In canonical Wnt signaling, β-catenin translocates to the nucleus to activate expression of Wnt-target genes, but β-catenin also anchors cadherin adhesion proteins to the cytoskeleton. Li et al . developed a mouse ( HSA– β -cat −/− ) selectively deficient in β-catenin in skeletal muscle cells. Whole-mount staining of diaphragms showed that whereas primary nerve branches were properly positioned at muscle fibers in control mice, they were misaligned in HSA– β -cat −/− mice. HSA– β -cat −/− mice also had fewer and longer secondary branches than did control mice. AChR clusters in HSA– β -cat −/− mice were larger and spread out over a wider area than those in control mice. Electrophysiological recordings revealed that HSA– β -cat −/− mice had a defect in spontaneous and depolarization-induced release of ACh from the presynaptic terminal but did not have any defect in postsynaptic AChR responsiveness. When this study was repeated in mice with a motoneuron-specific deficiency in β-catenin, no defects in NMJ morphology or function were found, which ruled out defective β-catenin-cadherin interactions as being responsible for the HSA– β -cat −/− phenotype. As Fu et al . speculate in commentary, one way that β-catenin in the muscle could regulate NMJ function is through driving the expression of genes that encode the retrograde signals needed for motoneuron differentiation. X.-M. Li, X.-P. Dong, S.-W. Luo, B. Zhang, D.-H. Lee, A. K. L. Ting, H. Neiswender, C.-H. Kim, E. Carpenter-Hyland, T.-M. Gao, W.-C. Xiong, L. Mei, Retrograde regulation of motoneuron differentiation by muscle β-catenin. Nat . Neurosci . 11 , 262-268 (2008). [PubMed] A. K. Y. Fu, Z. H. Cheung, N. Y. Ip, β-catenin in reverse action. Nat . Neurosci . 11 , 244-246 (2008). [PubMed]