MAP7 Prevents Axonal Branch Retraction by Creating a Stable Microtubule Boundary to Rescue Polymerization

Complex neural circuits are built from axonal branches that allow each neuron to connect with multiple targets. During development, maturation of nascent branches depends on stabilization of newly assembled or transported microtubules, which are thought to be regulated by microtubule-associated proteins (MAPs). However, because many known MAPs inhibit branch formation, it is not clear which MAP is responsible for regulating microtubule stability during branch development. Here, we show that MAP7, a less-well understood MAP that is localized to branch junctions, provides a key molecular mechanism to regulate microtubule stability during branch formation. In developing rodent sensory neurons of mixed sex, MAP7 is required for branch maturation mainly by preventing branch retraction. This function is mediated by the ability of MAP7 to control microtubule stability, as microtubules are more stable at branch junctions where MAP7 is localized. Consistently, nascent branches depleted of MAP7 have decreased stable microtubules but increased dynamic microtubules. Moreover, MAP7 binds to the acetylated and stable region of individual microtubules and avoids the dynamic plus end, thereby creating a boundary that prevents microtubule depolymerization and rescues microtubule polymerization. This unique binding property, which is not observed for other MAPs, can prevent branch retraction caused by laser-induced severing or nocodazole-induced microtubule depolymerization. Together, our study identifies a novel molecular mechanism mediated by MAP7 to regulate microtubule stability and strengthen branches at different stages of axonal branch morphogenesis.SIGNIFICANCE STATEMENT Development and maintenance of axonal branches rely on microtubule stability, but the underlying molecular mechanisms are not fully understood. Here, we show that MAP7, a unique protein that interacts with both microtubules and the motor protein kinesin-1, plays a key role at branch junctions. MAP7 stabilizes microtubules in nascent branches and prevents branch retraction during branch maturation or after laser-induced injury. MAP7 also binds to the acetylated region of microtubules to prevent depolymerization and rescue polymerization. This unique binding property supports a novel mechanism mediated by MAP7 to cooperate with other MAPs and control microtubule stability during axonal branch development. This mechanism could also impact microtubule regulation in branch regeneration after nerve injury.