Disease relevance of Dpysl2

• In dorsal root ganglion (DRG) organ culture, CRMP-2 overexpression by adenoviral vector demonstrated substantial neurite elongation [1].
• Studies determined for the first time whether collapsin response mediator protein-2 expression is altered in brain ischemia [2].
• Expression of wild type CRMP2 in primary hippocampal neurons or SH-SY5Y neuroblastoma cells promotes axon elongation [3].

Psychiatry related information on Dpysl2

• This is the first GSK3 substrate found to be regulated in this manner and may explain the hyperphosphorylation of CRMP2 observed in Alzheimer's disease [4].

High impact information on Dpysl2

• In addition to enumerating these S-nitrosylation sites, the method revealed endogenous SNO-Cys modification sites on cerebellum proteins, including alpha-tubulin, beta-tubulin, GAPDH, and dihydropyrimidinase-related protein-2 [5].
• Rat CRMP-2/TOAD-64 is most closely related to chick CRMP-62 and is the most widely expressed CRMP within the nervous system [6].
• Three additional lines of evidence support this possibility: TOAD-64 is upregulated following neuronal induction of P19 and PC12 cells; the protein is found in lamellipodia and filopodia of growth cones; and axotomy of the sciatic nerve induces reexpression [7].
• The expression of the TOAD-64 protein and gene coincident with initial neuronal differentiation and the downregulation when the majority of axon growth is complete suggests a role in axon elaboration [7].
• The data presented here suggest that TOAD-64 could be a central element in the machinery underlying axonal outgrowth and pathfinding, perhaps playing a role in the signal transduction processes that permit growing axons to choose correct routes and targets [7].

Biological context of Dpysl2

• The overexpression of Ras prevented the phosphorylation of CRMP-2 by GSK-3beta [8].
• Collectively, it would be plausible that CRMP-2 has potent nerve regeneration activity after nerve injury [1].
• Additionally, the expression of the dominant negative form of CRMP-2 or knockdown of the gene using small interference RNA (siRNA) mimics the effect of MAG in vitro [9].
• Since activation of PLC is thought to be associated with cell proliferation, we investigated whether group I mGluR agonist DHPG or subtype antagonists LY367385 and MPEP have an effect on dentate granule cells expressing immature neuronal marker TOAD-64 [10].
• The only sex difference in gene expression was found in the transcription of CRMP-2 gene [11].

Anatomical context of Dpysl2

• We previously showed that glycogen synthase kinase-3beta (GSK-3beta) is critical for specifying axon/dendrite fate by the regulation of the phosphorylation of collapsin response mediator protein-2 (CRMP-2) [8].
• While the sequence of TOAD-64 lacks a signal sequence and therefore is likely to encode a cytoplasmic protein, biochemical experiments demonstrate that the protein is tightly, but noncovalently, associated with membranes [7].
• The present study suggests that CRMP-2 has potent neurite elongation activity in nerve regeneration in vivo [1].
• CRMP-2-overexpressing motor neurons demonstrated the accelerated reprojection [1].
• Here we examined the role of CRMP-2 during nerve regeneration using rat hypoglossal nerve injury model [1].

Associations of Dpysl2 with chemical compounds

• The overexpression of the nonphosphorylated form of CRMP-2 at threonine 555, which is the phosphorylation site for Rho-kinase, counteracts the inhibitory effect of MAG on the postnatal cerebellar neurons [9].
• Turned on after devision-64 kD (TOAD-64), the identified protein, was present in all gels and, in addition, was up-regulated in the striata but not in the forebrains of the haloperidol-treated animals by 43% [12].
• Maternal dietary choline availability alters mitosis, apoptosis and the localization of TOAD-64 protein in the developing fetal rat septum [13].
• Several of the altered proteins (heat shock proteins 60 and 72, albumin, dihydropyrimidinase related protein-2, aldolase c, and malate dehydrogenase) have previously been connected to schizophrenia [14].
• Cdk5 phosphorylates CRMP-2 at serine 522, possibly facilitating phosphorylation of serine 518 and threonine 514 by glycogen synthase kinase 3beta (GSK3beta), a kinase previously implicated in Sema 3A signaling [15].

Other interactions of Dpysl2

• Taken together, these results suggest that Ras plays critical roles in establishing neuronal polarity upstream of the PI3-kinase/Akt/GSK-3beta/CRMP-2 pathway and mitogen-activated protein kinase cascade [8].
• In the N1E-115 cells, CRMP-2 has the most potent neurite elongation activity among the CRMP family members [1].
• The levels of 22 proteins, including dihydropyrimidinase-related proteins 1,3, and 4 and 14-3-3 proteins, were higher in the neonatal brain, whereas the levels of 28 proteins, including dihydropyrimidinase-related protein 2, dynamin-1 and many enzymes were higher in the adult brain [16].
• The mGluR1 antagonists LY367385 (10 microM, 72 h) markedly decreased the number of TOAD-64 positive cells and mGluR5 antagonist MPEP (1 microM, 72 h) had no effect [10].
• Significant higher CRMP-2 protein but not CRMP-4 protein was found in the hypothyroid rats [11].

Analytical, diagnostic and therapeutic context of Dpysl2

• Northern and in situ hybridization show that TOAD-64 mRNA is enriched in the nervous system and is developmentally regulated in parallel with the protein [7].
• Detection of TOAD-64 in adult rat brain as revealed by two-dimensional protein gel electrophoresis followed by MALDI mass spectrometry possible modulatory effect of chronic haloperidol treatment [12].

References