Role of GSK3 signaling in neuronal morphogenesis

Growing new neurons and axons sounds great. When do we get a practical application?
I need at least 171 million.
http://www.frontiersin.org/molecular_neuroscience/10.3389/fnmol.2011.00048/full

Glycogen synthase kinase 3 (GSK3) is emerging as a key regulator of several aspects of neuronal morphogenesis including neuronal polarization, axon growth, and axon branching. Multiple signaling pathways have been identified that control neuronal polarization, including PI3K, Rho-GTPases, Par3/6, TSC–mTOR, and PKA–LKB1. However, how these pathways are coordinated is not clear. As GSK3 signaling exhibits crosstalk with each of these pathways it has the potential to integrate these polarity signals in the control neuronal polarization. After neurons establish polarity, GSK3 acts as an important signaling mediator in the regulation of axon extension and axon branching by transducing upstream signaling to reorganization of the axonal cytoskeleton, especially microtubules. Here we review the roles of GSK3 signaling in neuronal morphogenesis and discuss the underlying molecular mechanisms.

During neural development, differentiated neurons undergo multiple steps of morphogenesis, including directed neuronal migration, neuronal polarization, axon outgrowth, axon guidance, and axon branching, to form the architectural basis of neural circuits. A common cellular process underlying these morphogenetic events is reorganization of the neuronal cytoskeleton directed by extracellular cues. Therefore, understanding how extracellular signals are translated into cytoskeletal reorganization is a key question in study of neuronal morphogenesis. Glycogen synthase kinase 3s (GSK3s), including GSK3α and GSK3β, are key components of the canonical Wnt signaling pathway. Recent studies indicate that GSK3s are also key upstream regulators of neuronal microtubules, as a number of microtubule-binding proteins (MBPs) are GSK3 substrates. Further, in addition to canonical Wnt ligands GSK3 activity is modulated by many other extracellular factors and their associated downstream pathways. Therefore, GSK3 is emerging as a major signaling mediator that functions to orchestrate each step of neuronal morphogenesis. In this review, we summarize and evaluate studies that show the involvement of GSK3 signaling in neuronal polarization, axon growth, and axon branching. We also discuss the potential molecular and cellular mechanisms by which GSK3 signaling regulates these morphogenetic processes.

GSK3 Signaling in Neuronal Polarization

The development of axon/dendrite polarity forms the structural basis for directional transmission of neural activities between neurons. In the past decade, the cellular and molecular mechanisms by which neuronal polarity is regulated have been extensively studied (Barnes and Polleux, 2009). Based on observations in a seminal in vitro model (Craig and Banker, 1994), we know that neuronal polarization involves multiple cellular steps. First, an intracellular signal is locally activated in one of the unpolarized neurites that breaks the cell symmetry and initiates the polarization process. Additional polarity determinants, likely downstream of the initiation signal, are then asymmetrically accumulated in the same neurite, which later becomes the axon. Second, such asymmetric signaling then triggers reorganization of cytoskeletal elements (actin filaments and microtubules) in the future axon and leads to its preferential growth. Lastly, sustained activation of multiple cellular processes specifically in the axon, including polarized protein/membrane transport and local protein translation/degradation, act to maintain the established asymmetry and axon extension. At the same time, complementary signaling occurs in the dendrites to suppress neurite extension. During the past decade, many intracellular signaling pathways and molecules have been identified that control these polarization steps. These include the PI3K pathway, the Rho-GTPase pathways, the Par3/6 pathway, the TSC–mTOR pathway, and the PKA–LKB1 pathway (Shi et al., 2003; Nishimura et al., 2004, 2005; Schwamborn and Puschel, 2004; Barnes et al., 2007; Shelly et al., 2007; Choi et al., 2008; Li et al., 2008). However, how these pathways regulate neuronal polarization in a coordinated manner is not clear. GSK3 signaling has been shown to crosstalk with each of these pathways, suggesting that it may function to coordinate and integrate polarity signaling. Here, we review the roles of GSK3 signaling and its potential link to established polarity pathways during each step of neuronal polarization