MAP7 Regulates Axon Collateral Branch Development in Dorsal Root Ganglion Neurons

Abstract

Collateral branches from axons are key components of functional neural circuits that allow neurons to connect with multiple synaptic targets. Like axon growth and guidance, formation of collateral branches depends on the regulation of microtubules, but how such regulation is coordinated to ensure proper circuit development is not known. Based on microarray analysis, we have identified a role for microtubule-associated protein 7 (MAP7) during collateral branch development of dorsal root ganglion (DRG) sensory neurons. We show that MAP7 is expressed at the onset of collateral branch formation. Perturbation of its expression by overexpression or shRNA knockdown alters axon branching in cultured DRG neurons. Localization and time-lapse imaging analysis reveals that MAP7 is enriched at branch points and colocalizes with stable microtubules, but enters the new branch with a delay, suggesting a role in branch maturation. We have also investigated a spontaneous mutant mouse that expresses a truncated MAP7 and found a gain-of-function phenotype both in vitro and in vivo. Further domain analysis suggests that the amino half of MAP7 is responsible for branch formation, suggesting a mechanism thatisindependentofitsknowninteractionwithkinesin.Moreover,thismouseexhibitsincreasedpainsensitivity,aphenotypethatisconsistent with increased collateral branch formation. Therefore, our study not only uncovers the first neuronal function of MAP7, but also demonstrates the importance of proper microtubule regulation in neural circuit development. Furthermore, our data provide new insights into microtubule regulation during axonal morphogenesis and may shed light on MAP7 function in neurological disorders.

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

“…In vitro, MAP7 competes with another MAP, tau, and directly enhances kinesin‐1 binding to the microtubule, but inhibits kinesin‐3 from accessing the microtubule (Monroy et al, ). Recently, MAP7 was found to be up‐regulated during collateral branch formation in dorsal root ganglion (DRG) neurons, and overexpression of MAP7 led to a dramatic increase in the number of collateral branches (Tymanskyj et al, ). Together these results suggest that MAP7 is involved both in kinesin‐1‐based transport and microtubule organization in a variety of cell types.…”

“…Article is online at: http://onlinelibrary.wiley.com/doi/10.1002/dvdy. 24599/abstract V C 2017 Wiley Periodicals, Inc. development and activity (Papasozomenos et al, 1985;Caceres and Kosik, 1990;Bulinski et al, 1997;Gleeson et al, 1999a;Gordon-Weeks and Fischer, 2000;Volle et al, 2013;Tymanskyj et al, 2017).…”

MAP7 recruits kinesin-1 to microtubules to direct organelle transport

“…MAP7 promotes binding of kinesin-1 to microtubules to enable a range of kinesin-1 mediated roles, including intracellular transport, oocyte polarization, nuclear positioning, and centrosome separation (18,19,(21)(22)(23)(24)35). Given its central role in regulating kinesin-1 activity, we sought to uncover the mechanisms through which MAP7 controls organelle transport.…”

“…Tau localizes throughout the axon, but is enriched in the distal axon (40). MAP7 localizes to axonal branches, and contributes to branch formation (18,19). Interestingly, MAP7 has been shown to compete with tau for binding along the microtubule lattice (23), such that tau and MAP7 may enrich on discrete regions of the microtubule cytoskeleton where they perform distinct functions.…”

“…MAP7 is a microtubule-associated protein involved in a diverse array of cellular processes. By serving as a microtubule polymerase (18,19), MAP7 enhances neuronal branching and controls the spindle length (20). MAP7 strongly affects kinesin-1 motility.…”