Neuronal polarity: demarcation, growth and commitment

Abstract

In a biological sense, polarity refers to the extremity of the main axis of an organelle, cell, or organism. In neurons, morphological polarity begins with the appearance of the first neurite from the cell body. In multipolar neurons, a second phase of polarization occurs when a single neurite initiates a phase of rapid growth to become the neuron's axon, while the others later differentiate as dendrites. Finally, during a third phase, axons and dendrites develop an elaborate architecture, acquiring special morphological and molecular features that commit them to their final identities. Mechanistically, each phase must be preceded by spatial restriction of growth activity. We will review recent work on the mechanisms underlying the polarized growth of neurons.

Figure 1. The three phases of neuron polarization

Phase I first neurite formation. The model is based on studies in Drosophila sensory neurons in the notum and hippocampal neurons in culture. In the fly, the newborn neuron “inherits” remnants from the cytokinesis ring (red) with the ability to induce localized cytoskeletal changes (e.g., via RhoA and Aurora kinase) and the recruitment of PI (4,5) P2 (light blue). This, in turn, triggers the clustering and activation of polarity-complex proteins, leading to the formation of a cell-cell adhesive ring (purple). This cascade of events results in the generation of an apical plasma membrane domain from where the first neurite grows. In hippocampal neurons this process is critical to define growth axis in vivo. Cytoplasmic organelles, such as Golgi and centrioles, move toward the growing neurite after this has formed. Phase II: axon specification. At stage 2, all minor neurites have minimal machinery to support fast growth. Filamentous actin (blue) is assembled at the tip of each neurite, and microtubules are oriented uniformly with the plus-end pointing to the distal (“plus-end-distal” microtubules are shown in orange). A RhoA-inhibitory tone prevents the transformation of minor neurites into fast-growing axon-like neurites. Removal of this inhibitory tone in one neurite enhances the dynamics of actin cytoskeleton and leads to fast growth, which transforms the neurite into an axon (stage 3). This process may be determined through an external cue or occur by a cell-autonomous mechanism. Phase III: The nascent axon and dendrites of a neuron are committed to distinct developmental paths to be transformed into their final architecture. During stage 4, the remaining minor neurites are transformed into dendrites. “Minus-end-distal” microtubules (green) and Golgi outposts appear in the dendrites, but not the axon. Except for length, at this stage the morphology of nascent dendrites and axons is similar. Through both preexisting differences that arise during the time of axon-dendrite specification and de novo mechanisms, axons and dendrites develop the dramatically distinct characteristics of mature neurons (stage 5).