Article

Collapsin-Induced Growth Cone Collapse Mediated by an Intracellular Protein Related to Unc-33

Yale University, New Haven, Connecticut, United States
Nature (Impact Factor: 41.46). 09/1995; 376(6540):509-14. DOI: 10.1038/376509a0
Source: PubMed

ABSTRACT

Collapsin, a member of the newly recognized semaphorin family, contributes to axonal pathfinding during neural development by inhibiting growth cone extension. The mechanism of collapsin action is poorly understood. Here we use a Xenopus laevis oocyte expression system to identify molecules involved in collapsin signalling, because several experiments have raised the possibility that heterotrimeric GTP-binding proteins might participate in these events. A collapsin response mediator protein of relative molecular mass (M(r)) 62K (CRMP-62) required for collapsin-induced inward currents in X. laevis oocytes is isolated. CRMP-62 shares homology with UNC-33, a nematode neuronal protein required for appropriately directed axonal extension. CRMP-62 is localized exclusively in the developing chick nervous system. Introduction of anti-CRMP-62 antibodies into dorsal root ganglion neurons blocks collapsin-induced growth cone collapse. CRMP-62 appears to be an intracellular component of a signalling cascade initiated by an unidentified transmembrane collapsin-binding protein.

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    • "The formation, maturation, and maintenance of dendritic spines are tightly regulated by different extracellular signals including semaphorin 3A (Sema3A). Collapsin response mediator proteins (CRMPs), initially identified as a signaling molecule of Sema3A [1], are composed of five homologous cytosolic phosphoproteins (CRMP1–5) and are highly expressed in developing and adult nervous systems [2] [3] [4] [5]. CRMPs bind with tubulin heterodimers, whereas the sequential phosphorylation of CRMPs lowers their binding affinity to tubulin [6]. "
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    ABSTRACT: Proper density and morphology of dendritic spines are important for higher brain functions such as learning and memory. However, our knowledge about molecular mechanisms that regulate the development and maintenance of dendritic spines is limited. We recently reported that cyclin-dependent kinase 5 (Cdk5) is required for the development and maintenance of dendritic spines of cortical neurons in the mouse brain. Previous in vitro studies have suggested the involvement of Cdk5 substrates in the formation of dendritic spines; however, their role in spine development has not been tested in vivo. Here, we demonstrate that Cdk5 phosphorylates collapsin response mediator protein 2 (CRMP2) in the dendritic spines of cultured hippocampal neurons and in vivo in the mouse brain. When we eliminated CRMP2 phosphorylation in CRMP2 KI/KI mice, the densities of dendritic spines significantly decreased in hippocampal CA1 pyramidal neurons in the mouse brain. These results indicate that phosphorylation of CRMP2 by Cdk5 is important for dendritic spine development in cortical neurons in the mouse hippocampus.
    Full-text · Article · Jul 2015 · Neural Plasticity
    • "Semaphorin 3A is a typical repulsive guidance molecule for axons, and it is secreted to induce growth cone collapse and axon retraction (Nakamura et al., 2000). The members of the collapsin response mediator protein (CRMP) family (CRMP1–5) were originally identified as intracellular signaling mediators of semaphorin 3A-induced growth cone collapse (Goshima et al., 1995). Since then, CRMPs have been shown to be expressed and function in developing and adult brains (Charrier et al., 2003; Bretin et al., 2005; Veyrac et al., 2005, 2011; Laeremans et al., 2013). "
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    ABSTRACT: Members of the collapsin response mediator protein (CRMP) family are reported to be involved in the pathogenesis of various neuronal disorders including schizophrenia and autism. One of them, CRMP4, is reported to participate in aspects of neuronal development such as axonal guidance and dendritic development. However, no physiological or behavioral phenotypes in Crmp4 knockout (Crmp4-KO) mice have been identified, making it difficult to elucidate the in vivo roles of CRMP4. Focusing on the olfaction process because of our previous study showing strong expression of Crmp4 mRNA in the olfactory bulb during the early postnatal period, we aimed to test the hypothesis that Crmp4-KO pups would exhibit abnormal olfaction. Based on measurements of their ultrasonic vocalizations, we found impaired olfactory ability in Crmp4-KO pups. In addition, c-Fos expression, a marker of neuron activity, revealed hyperactivity in the olfactory bulb of Crmp4-KO pups compared with wild types following exposure to an odorant. Moreover, the mRNA and protein expression levels of GluR1 and GluR2 were exaggerated in Crmp4-KO pups relative to other excitatory and inhibitory receptors and transporters, raising the possibility that enhanced expression of these excitatory receptors contributes to the hyperactivity phenotype and impairs olfactory ability. This study provides evidence for an animal model for elucidating the roles of CRMP4 in the development of higher brain functions as well as for elucidating the developmental regulatory mechanisms controlling the activity of the neural circuitry. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · European Journal of Neuroscience
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    • "For more detailed experimental validation studies, we focused our efforts on the protein CRMP1, whose transcript levels are significantly diminished in HD brains (Fig. 1B). CRMP1 is a cytoplasmic phosphoprotein that is predominantly expressed in neurons (Goshima et al. 1995). Previous studies revealed that mice lacking CRMP1 show impairment of learning and memory (Su et al. 2007), suggesting that a reduction of CRMP1 levels in HD brains might contribute to the disease phenotype (Paulsen et al. 2013). "
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    ABSTRACT: Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins. © 2015 Stroedicke et al.; Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Apr 2015 · Genome Research
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