Slit2 as a β-catenin/Ctnnb1-dependent retrograde signal for presynaptic differentiation.
Slit2 as a β-catenin/Ctnnb1-dependent retrograde signal for presynaptic differentiation.
复制标题
Slit2 作为突触前分化的 β-catenin/Ctnnb1 依赖性逆行信号。
作者：
Wu H;Barik A;Lu Y;Shen C;Bowman A;Li L;Sathyamurthy A;Lin TW;Xiong WC;Mei L
Neuromuscular junction formation requires proper interaction between motoneurons and muscle cells. β-Catenin (Ctnnb1) in muscle is critical for motoneuron differentiation; however, little is known about the relevant retrograde signal. In this paper, we dissected which functions of muscle Ctnnb1 are critical by an in vivo transgenic approach. We show that Ctnnb1 mutant without the transactivation domain was unable to rescue presynaptic deficits of Ctnnb1 mutation, indicating the involvement of transcription regulation. On the other hand, the cell-adhesion function of Ctnnb1 is dispensable. We screened for proteins that may serve as a Ctnnb1-directed retrograde factor and identified Slit2. Transgenic expression of Slit2 specifically in the muscle was able to diminish presynaptic deficits by Ctnnb1 mutation in mice. Slit2 immobilized on beads was able to induce synaptophysin puncta in axons of spinal cord explants. Together, these observations suggest that Slit2 serves as a factor utilized by muscle Ctnnb1 to direct presynaptic differentiation. DOI: http://dx.doi.org/10.7554/eLife.07266.001 Motor nerves are like electrical wires that connect our spinal cord to the muscles in our body. These nerves communicate with muscles across a connection called the neuromuscular junction. To first form a neuromuscular junction, the motor nerves and muscles each produce molecular cues that tell each other to do their part to build a connection. Beta-catenin in the muscle is known to regulate motor nerve development. However, beta-catenin has two different roles: it helps to coordinate whether neighboring cells stick together, and it can regulate which genes are ‘transcribed’ to produce proteins. It was not known which of these roles is necessary for forming neuromuscular junctions. Wu, Barik et al. now investigate this question by creating mice with mutant forms of beta-catenin in their muscles. Some mice had muscle beta-catenin that could not help cells stick together, and others had beta-catenin that could not control gene transcription. Only mutations that affected the ability of beta-catenin to control transcription caused abnormalities in the neuromuscular junction. However, these problems could be fixed by adding either normal beta-catenin or the mutant form that cannot help cells stick together. Wu, Barik et al. then used molecular tools to explore which genes are turned on by beta-catenin. The experiments showed that beta-catenin causes muscle fibers to produce a protein called Slit2—a developmental cue that controls where neurons grow. Furthermore, the neuromuscular junction defects found in mice without beta-catenin in their muscles could be reduced by making the muscle fibers produce more Slit2. However, not all defects in beta-catenin mutant mice are rescued by Slit2. Future research is needed to identify other beta-catenin-controlled signals and to determine whether such a pathway is altered in neuromuscular disorders. DOI: http://dx.doi.org/10.7554/eLife.07266.002
