Microtubule plus-end tracking proteins in neuronal development

Abstract

Regulation of the microtubule cytoskeleton is of pivotal importance for neuronal development and function. One such regulatory mechanism centers on microtubule plus-end tracking proteins (+TIPs): structurally and functionally diverse regulatory factors, which can form complex macromolecular assemblies at the growing microtubule plus-ends. +TIPs modulate important properties of microtubules including their dynamics and their ability to control cell polarity, membrane transport and signaling. Several neurodevelopmental and neurodegenerative diseases are associated with mutations in +TIPs or with misregulation of these proteins. In this review, we focus on the role and regulation of +TIPs in neuronal development and associated disorders.

Keywords: CLASP; CLIP; Cytoskeleton; Development; EB; Microtubule; Neuron; Plus-end tracking proteins; Polarity.

Fig. 1

Microtubule organization and function during neurodevelopment. Cultured dissociated neurons start out as spherical, unpolarized cells with MTs oriented with their plus-ends towards the plasma membrane (a). Upon symmetry breaking, neurite extension is thought to be facilitated by motor proteins, which were proposed to push MTs and thus exert a force on the membrane to form protrusions (b). Young neurons possess multiple neurites and maintain a mainly plus-end out MT orientation (c). While remaining neurites cycle between phases of growth and shrinkage, one neurite rapidly extends to form the axon. In this neurite, MTs become stabilized and MT bundles are decorated with the axon-specific MAP tau, while MTs remain oriented plus-end out. The rate of advance and the directionality of axon outgrowth is controlled by the growth cone, a specialized structure at the tip of the axon that contains a dynamic array of MTs. Local stabilization of a MT in one of the filopodia of the growth cone prompts the growth cone to turn in that direction (d). Later in development, the remaining neurites differentiate into dendrites. Dendrites acquire unique antiparallel MT bundles decorated by MAP2, presumably contributing to selective cargo trafficking (e). The post-synapse is present at the tips of dendritic spines. Targeting of dynamic MTs to spines triggers morphological changes and alters synaptic strength, possibly by allowing the delivery of specific cargo to the spine or activating signaling processes (f)