Beyond Neuronal Microtubule Stabilization: MAP6 and CRMPS, Two Converging Stories

Abstract

The development and function of the central nervous system rely on the microtubule (MT) and actin cytoskeletons and their respective effectors. Although the structural role of the cytoskeleton has long been acknowledged in neuronal morphology and activity, it was recently recognized to play the role of a signaling platform. Following this recognition, research into Microtubule Associated Proteins (MAPs) diversified. Indeed, historically, structural MAPs—including MAP1B, MAP2, Tau, and MAP6 (also known as STOP);—were identified and described as MT-binding and -stabilizing proteins. Extensive data obtained over the last 20 years indicated that these structural MAPs could also contribute to a variety of other molecular roles. Among multi-role MAPs, MAP6 provides a striking example illustrating the diverse molecular and cellular properties of MAPs and showing how their functional versatility contributes to the central nervous system. In this review, in addition to MAP6’s effect on microtubules, we describe its impact on the actin cytoskeleton, on neuroreceptor homeostasis, and its involvement in signaling pathways governing neuron development and maturation. We also discuss its roles in synaptic plasticity, brain connectivity, and cognitive abilities, as well as the potential relationships between the integrated brain functions of MAP6 and its molecular activities. In parallel, the Collapsin Response Mediator Proteins (CRMPs) are presented as examples of how other proteins, not initially identified as MAPs, fall into the broader MAP family. These proteins bind MTs as well as exhibiting molecular and cellular properties very similar to MAP6. Finally, we briefly summarize the multiple similarities between other classical structural MAPs and MAP6 or CRMPs.In summary, this review revisits the molecular properties and the cellular and neuronal roles of the classical MAPs, broadening our definition of what constitutes a MAP.

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

“…Cofilin-actin rod pathology, significantly more prevalent in brains of human AD subjects compared to controls [42,295], is found in brains of AD but not WT mice [97]. Defects in axonal transport characterize early stages of many neurodegenerative diseases, and rod formation impairs vesicular transport [276,296], which can be regained after reversal of rods by the removal of the inducer [277,285]. Observation of rods in live cells utilizes a genetically encoded rod reporter made from a point mutation in cofilin (R21Q) that allows rod association without inducing rod formation through its overexpression.…”

Microtubule remodelling as a driving force of axon guidance and pruning

“…Early on, structural MAPs have been defined as proteins that can be co-purified with MTs and that have the ability to promote the assembly and stabilisation of these polymers. However, during the past 20 years, the extensive characterisation of neuronal MAPs has gradually expanded their functional diversity, unravelling among others their roles as key MT/actin crosslinkers [24,117] and as signalling molecules in developing neurons [118].…”

Neurons as a model system for cryo-electron tomography

“…A recent in vitro cryo-ET publication has brought strong evidence that microtubule-associated protein 6 (MAP6, also known as stable tubule-only peptide), a large protein know for providing stability to microtubules is one of the main components of the intralumenal particles and shed light on their function ( Cuveillier et al, 2020 ). MAP6 is an intrinsically disordered protein and it was the first neuronal microtubule-associated protein to be discovered ( Cuveillier et al, 2021 ). It stabilizes neuronal microtubules, and can interact with membranes, as well as with actin.…”