Signaling Networks in Neuronal Polarization

Abstract

A mature neuron is typically polarized both structurally and functionally, with a single long axon and several dendrites. Neuronal polarity is essential for unidirectional signal flow from somata or dendrites to axons. The initial event in establishing a polarized neuron is the specification of a single axon. Early in neuronal development, one immature neurite becomes differentiated from other neurites to form an axon. Although studies in the past two decades have yielded a catalog of structural, molecular, and functional differences between axons and dendrites, we are only now beginning to understand the molecular mechanisms involved in the establishment of neuronal polarity.In the last few years, neuronal polarity-regulating molecules have been revealed. There are two major signaling cascades in neuronal polarization. Several groups, including ours, reported that the phosphatidylinositol 3-kinase (PI3-kinase)/Akt/glycogen synthase kinase-3␤ (GSK-3␤)/collapsin response mediator protein-2 pathway is important for axon specification and elongation. Recent studies have revealed that the positive feedback loop composed of Rho family small GTPases and the Par3/Par6/atypical protein kinase C complex plays a role in the initial events of neuronal polarization downstream of PI3-kinase. Here, we discuss the roles of signaling molecules for axon specification. Key words: axon; neuronal polarity; PI3-kinase; GSK-3␤; CRMP-2; Par complex Processes of neuronal polarizationThe ability of neuronal cells to polarize is essential for organization of the nervous system. A model system for studying neuronal polarity, cultured hippocampal neurons, was pioneered by Craig and Banker (1994) Ͼ20 years ago. Cultured hippocampal neurons develop a single long axon and several shorter dendrites, which maintain their structural characteristics at the molecular level. During maturation, hippocampal neurons dramatically change their morphology. Dotti et al. (1988) precisely observed this differentiation process and divided the morphological events into five stages (Fig. 1). Shortly after attachment to the substratum, a neuron extends lamellipodia (stage 1). These protrusions then develop into several short immature neurites (stage 2). At this stage, neurons still appear to be unpolarized. All neurites alternate phases of elongation and retraction and are approximately equal in length. It is difficult to determine which neurite will become an axon. Next, one of the immature neurites rapidly grows into a long neurite, which soon acquires axonal characteristics (stage 3). A few days after the formation of the axon, the remaining neurites slowly elongate to become dendrites (stage 4). Typically, the axon and dendrites continue to mature and subsequently develop by 7 d after plating. Cultured neurons form synaptic contacts and establish a neuronal network (stage 5).Neuronal polarization occurs from stage 2 to stage 3. The first step in neuronal polarization is initial axon formation. The specification of the axon is thought to depend on its length...

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“…Calcium-mediated pathways of Ras activation might be a critical mechanism to couple rapid and transient neuronal electrical activity with long-term changes in nervous system development and function (36)(37)(38)(39)(40). The small GTPase protein Ras couples calcium influx to many forms of synaptic plasticity, including rapid synaptic potentiation and new synapse formation.…”

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“…Th ere are two essential PI3K signaling cascades in neuronal polarization (Figure 4). PI3K/Akt kinase/glycogen synthase kinase-3β (GSK-3β) and the positive feedback loop PI3K/Rho GTPases/partitioning-defective proteins 3 and 6/atypical PKC (Par3-Par6-aPKC complex) (Yoshimura et al 2006). PI3K is responsible for the synthesis of phosphatidylinositol-3,4,5-triphosphate (PIP3), which is then accumulated in the growth cones of developing axons (Shi et al 2003).…”

“…Two pathways are depicted. PI3K -phosphoinositide 3-kinase; PIP3 -phosphatidylinositol-3,4,5-triphosphate; Akt -kinase; GSK-3β -glycogen synthase kinase-3β; CRMP-2 -collapsin response mediator protein-2; MAP1B -microtubule-associated protein 1B; Cdc42 -cell division control protein 42, Par3-Par6-aPKC complex -partitioning-defective proteinsmediator protein-2 (CRMP-2), which in its active form promotes tubulin polymerization and inhibits retraction of new polarized tubulin fi laments (Yoshimura et al 2006). Similarly, activated GSK-3β negatively regulates the function of microtubule-associated protein 1B (MAP1B), which interacts with microtubules and supports microtubule stability in growing axon (Trivedi et al 2005).…”

“…A constitutively active GSK-3β mutants, which inhibited axon formation and decreased activity of GSK-3β, are important assumptions for the axon elongation (Jiang et al 2005). Hypothesis of a positive feedback loop is based on the theory that PI3K activates via PIP3 several small GTPases belonging to Rho GTPase family, which are able to activate PI3K by an indirect positive feedback in cooperation with Par3-Par6-aPKC complex (Yoshimura et al 2006;Yang et al 2012). Downstream intracellular signalization of PI3K is well known, however, upstream signalization from extracellular environment is indistinct and widely discussed.…”

“…Downstream intracellular signalization of PI3K is well known, however, upstream signalization from extracellular environment is indistinct and widely discussed. While some studies consider tyrosine kinase receptor (Trk)/growth factor's signalization to be an extracellular trigger mechanism of PI3K activation, others support theory about the laminin or neuron-glia cell adhesion molecule and lamellipodia interaction (Da Silva et al 2005;Menager et al 2004;Yoshimura et al 2006;Tahirovic and Bradke 2009). …”