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

Abstract

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.

Concerted action of kinesins KIF5B and KIF13B promotes efficient secretory vesicle transport to microtubule plus ends

“…MAP7 and its homologues are more abundant on older MTs, apparently because of their slow association with growing MTs. In COS7 cells, where MTs are more dynamic than in HeLa cells studied here, overexpressed GFP-MAP7 was reported to form a sharp boundary along the MT shaft, associated with the end of the stable MT segment (Tymanskyj and Ma, 2019). It can be expected that in cells with highly dynamic MTs, Rab6 transport to MT plus ends will be more dependent on kinesin-3 family members.…”

Concerted action of kinesins KIF5B and KIF13B promotes efficient secretory vesicle transport to microtubule plus ends

“…MAP7 and its homologues are more abundant on older MTs, apparently because of their slow association with growing MTs. In COS7 cells, where MTs are more dynamic than in the HeLa cells studied here, overexpressed GFP-MAP7 was reported to form a sharp boundary along the MT shaft, associated with the end of the stable MT segment ( Tymanskyj and Ma, 2019 ). It can be expected that in cells with highly dynamic MTs, Rab6 transport to MT plus ends will be more dependent on kinesin-3 family members.…”

A Combinatorial MAP Code Dictates Polarized Microtubule Transport

“…MAP7 also has kinesin-independent roles in regulating microtubule dynamics (Gallaud et al, 2014;Mé tivier et al, 2019;Tymanskyj et al, 2017) and is important to promote axonal branch regeneration after nerve injury (Tymanskyj and Ma, 2019). Whether MAP9 has roles in regulating the microtubule cytoskeleton that are independent of its roles in directing motors or whether MAP7 and MAP9 coordinate their binding activities to regulate microtubule dynamics remains to be determined.…”