MAPs of the neuron: Exploring the role of microtubule-associated proteins in neurodevelopment

Abstract

The microtubule cytoskeleton is essential for nearly every stage of neurodevelopment, fromdifferentiation,migration, polarization, axon and dendrite development to synapse connections.During these processes, microtubules serves as ‘roads’ for motor proteins mediated cargotransport over long distances. As the neuron from human PNS can have axons with a totallength ranging from 10 mm to 100 m, the microtubule based motors transport life sustainingmaterials such as organelles, proteins or mRNAs from the soma to the axon terminal. Neurons express abundant MAPs to regulate the microtubule cytoskeleton. MAPs were initially defined as proteins that bind to and stabilize microtubules. More recently it is becoming clear that MAPs can regulate the microtubule network in many other ways, which will be explored in this thesis. In chapter 2 we describe the emerging concept that regionally confined MAPs act as a “MAP code” regulating motor activity. We found that MAP7 family members MAP7/7D1 are specifically enriched in somatodendritic compartment of the neuron, whereas MAP7D2 localizes in the proximal axon and promotes Kinesin-1 mediated cargo transport into axons. In chapter 3 we discussed how the E3 ubiquitin ligase family members MID1 and MID2 associate with microtubule cytoskeleton and control axon and dendrite development. In chapter 4 we show how MAPs act as microtubule crosslinkers to form the proximal axon specific microtubule fascicles. In chapter 5 we discuss the cross-talk between TRIM46 induced parallel microtubules and the AnkG mediated submembrane domain coordinate to drive theAIS assembly to establish neuronal polarity. In chapter 6 we discuss the mechanisms that underlie the specific microtubule organization in axons; the “MAP code” that guide Kinesin-1 with cargos out of dendrites and into axons; the mechanisms of how MAPs are confined to different compartments of neurons and how MAPs regulate axon branching.