Article

Protease Regulation: The Yin and Yang of Neural Development and Disease

Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Neuron (Impact Factor: 15.05). 10/2011; 72(1):9-21. DOI: 10.1016/j.neuron.2011.09.012
Source: PubMed

ABSTRACT

The formation, maintenance, and plasticity of neural circuits rely upon a complex interplay between progressive and regressive events. Increasingly, new functions are being identified for axon guidance molecules in the dynamic processes that occur within the embryonic and adult nervous system. The magnitude, duration, and spatial activity of axon guidance molecule signaling are precisely regulated by a variety of molecular mechanisms. Here we focus on recent progress in understanding the role of protease-mediated cleavage of guidance factors required for directional axon growth, with a particular emphasis on the role of metalloprotease and γ-secretase. Since axon guidance molecules have also been linked to neural degeneration and regeneration in adults, studies of guidance receptor proteolysis are beginning to define new relationships between neurodevelopment and neurodegeneration. These findings raise the possibility that the signaling checkpoints controlled by proteases could be useful targets to enhance regeneration.

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    • "Many axon guidance receptors are proteolytically cleaved at their juxta-membrane region by membrane-associated metalloproteases of the ADAM (A disintegrin and metalloprotease) family , leading to the shedding of their ectodomains. This shedding is required for proper axon guidance and controls receptor levels, activation, and the disassembly of ligand-receptor complexes (Bai and Pfaff, 2011). Despite these important roles, how the neuronal effects of ADAMs are controlled to regulate axon guidance receptor signaling remains incompletely understood . "
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    ABSTRACT: Many guidance receptors are proteolytically cleaved by membrane-associated metalloproteases of the ADAM family, leading to the shedding of their ectodomains. Ectodomain shedding is crucial for receptor signaling and function, but how this process is controlled in neurons remains poorly understood. Here, we show that the transmembrane protein Lrig2 negatively regulates ADAM-mediated guidance receptor proteolysis in neurons. Lrig2 binds Neogenin, a receptor for repulsive guidance molecules (RGMs), and prevents premature Neogenin shedding by ADAM17 (TACE). RGMa reduces Lrig2-Neogenin interactions, providing ADAM17 access to Neogenin and allowing this protease to induce ectodomain shedding. Regulation of ADAM17-mediated Neogenin cleavage by Lrig2 is required for neurite growth inhibition by RGMa in vitro and for cortical neuron migration in vivo. Furthermore, knockdown of Lrig2 significantly improves CNS axon regeneration. Together, our data identify a unique ligand-gated mechanism to control receptor shedding by ADAMs and reveal functions for Lrigs in neuron migration and regenerative failure.
    Full-text · Article · Dec 2015 · Developmental Cell
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    • "Here, we review the basic roles and mechanisms of local protein synthesis in axon guidance and discuss recent findings that localized translational control is involved in guidance decisions in vivo. A comprehensive review of axon guidance is beyond the scope of this review, and the reader is referred to several excellent recent reviews that cover this topic (Mortimer et al., 2008; Quinn and Wadsworth, 2008; Geraldo and Gordon- Weeks, 2009; Bai and Pfaff, 2011; Kolodkin and Tessier-Lavigne, 2011; Tojima et al., 2011; Vitriol and Zheng, 2012; Dudanova and Klein, 2013). "
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    ABSTRACT: Axon guidance plays a key role in establishing neuronal circuitry. The motile tips of growing axons, the growth cones, navigate by responding directionally to guidance cues that pattern the embryonic neural pathways via receptor-mediated signaling. Evidence in vitro in the last decade supports the notion that RNA-based mechanisms contribute to cue-directed steering during axon guidance. Different cues trigger translation of distinct subsets of mRNAs and localized translation provides precise spatiotemporal control over the growth cone proteome in response to localized receptor activation. Recent evidence has now demonstrated a role for localized translational control in axon guidance decisions in vivo.
    Full-text · Article · Sep 2013 · The Journal of Cell Biology
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    • "Indeed, several cell surface receptors and proteins including Notch 1, ERBB4, Robo, N-cadherins, neuregulins, P75NTR, LRP1, APLP1, and APLP2, among others, are also cleaved by secretases . Secretase-mediated cleavage of these proteins results in the production of extracellular and intracellular fragments with unique physiological functions (De Strooper et al., 1999; Ni et al., 2001; Reiss et al., 2005; Scheinfeld et al., 2002; reviewed by Bai and Pfaff, 2011). The similarity of APP structure and processing with many of these receptors suggests that APP might also act as a cell surface receptor with specialized functions; however, natural physiological ligands for APP remain elusive. "
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    ABSTRACT: A role of amyloid β (Aβ) peptide aggregation and deposition in Alzheimer's disease (AD) pathogenesis is widely accepted. Significantly, abnormalities induced by aggregated Aβ have been linked to synaptic and neuritic degeneration, consistent with the "dying-back" pattern of degeneration that characterizes neurons affected in AD. However, molecular mechanisms underlying the toxic effect of aggregated Aβ remain elusive. In the last 2 decades, a variety of aggregated Aβ species have been identified and their toxic properties demonstrated in diverse experimental systems. Concurrently, specific Aβ assemblies have been shown to interact and misregulate a growing number of molecular effectors with diverse physiological functions. Such pleiotropic effects of aggregated Aβ posit a mayor challenge for the identification of the most cardinal Aβ effectors relevant to AD pathology. In this review, we discuss recent experimental evidence implicating amyloid β precursor protein (APP) as a molecular target for toxic Aβ assemblies. Based on a significant body of pathologic observations and experimental evidence, we propose a novel pathologic feed-forward mechanism linking Aβ aggregation to abnormalities in APP processing and function, which in turn would trigger the progressive loss of neuronal connectivity observed early in AD.
    Full-text · Article · May 2013 · Neurobiology of aging
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