Involvement of membrane protein GDE2 in retinoic acid-induced neurite formation in Neuro2A cells

Department of Molecular and Applied Bioscience, Graduate School of Biosphere Science, Hiroshima University, 4-4, Kagamiyama 1-chome, Higashi-Hiroshima 739-8528, Japan.
FEBS Letters (Impact Factor: 3.17). 03/2007; 581(4):712-8. DOI: 10.1016/j.febslet.2007.01.035
Source: PubMed


We show that a glycerophosphodiester phosphodiesterase homolog, GDE2, is widely expressed in brain tissues including primary neurons, and that the expression of GDE2 in neuroblastoma Neuro2A cells is significantly upregulated during neuronal differentiation by retinoic acid (RA) treatment. Stable expression of GDE2 resulted in neurite formation in the absence of RA, and GDE2 accumulated at the regions of perinuclear and growth cones in Neuro2A cells. Furthermore, a loss-of-function of GDE2 in Neuro2A cells by RNAi blocked RA-induced neurite formation. These results demonstrate that GDE2 expression during neuronal differentiation plays an important role for growing neurites.

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    • "Neuro2a cells were seeded onto 48-well culture plates precoated with poly-l-ornithine solution (15 ␮g/mL). P2Y13 receptor antagonist was applied 30 min before addition of RA (40 ␮M) [22] [39] [40]. The cells were fixed with 4% paraformaldehyde 48 h after application of reagents and retinoic acid, and viewed under a fluorescence microscope BZ-9000 (KEYENCE, Osaka, Japan). "
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    ABSTRACT: We examined the receptor-mediated effects of extracellular ATP on neuronal differentiation of PC12 cells, Neuro2a cells and MEB5 cells by using a series of receptor antagonists. The P2Y13 receptor antagonist MRS2211 significantly accelerated neurite outgrowth in all cases. Treatment with nerve growth factor (NGF) alone activated ERK1/2 in PC12 cells, and the activation was further increased by MRS2211. These results suggest involvement of P2Y13 receptor in suppression of neuronal differentiation. Thus, P2Y13 receptor antagonists might be candidates for treatment of neurodegenerative diseases.
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    • "Then mouse GDE2 and GDE6 were isolated and their tissue distributions were characterized [15]. Recently, mouse GDE2 was demonstrated to play an important role for growing neuritis and osmotically regulate the osmoprotective organic osmolyte glycerophosphocholine [16] [17]. To date, seven mammalian GDEs have been virtually cloned based on bioinformatics analysis [18]. "
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    ABSTRACT: As a transmembrane protein family, glycerophosphodiester phosphodiesterase (GDPD/GDE) catalyzes the hydrolysis of deacylated glycerophospholipids to glycerol phosphate and alcohol. To date, seven mammalian GDEs have been virtually cloned or predicted by bioinformatics analysis, however, GDE4 has not been molecular isolated and characterized in mammal. Here we report molecular cloning of human GDE4 encoding cDNA sequence, which is 945 base pairs long encoding a 314-amino acid protein with 2 transmembrane regions and a GDE motif. The human GDE1 gene is located on chromosome 19q22 and contains ten exons and nine introns. A molecular 3-D model provides the first structural information of human GDE4 and suggests a triose-phosphate-isomerase barrel core as typically found in bacterial GDPDs. Furthermore, a model of the putative catalytic residues highlights that the individual core residues Glu72, Asp74, and His87 are crucial to maintaining GDE4 catalytic activity. Western blotting shows that human GDE4 is a 36 kDa protein. Subcellular localization of GDE4 tagged with enhanced green fluorescence protein is in the cytoplasm, especially accumulated in the perinuclear region and the cell periphery. Moreover, over-expression of GDE4 did not induce neurite formation or change cell morphology. These results indicate GDE4 protein is a member of the GDE family and suggest it may play different roles from other members of GDE family.
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    ABSTRACT: Bacterial glycerophosphodiester phosphodiesterases (GP-PDEs), GlpQ and UgpQ, are well-characterized periplasmic and cytosolic proteins that play critical roles in the hydrolysis of deacylated glycerophospholipids to glycerol phosphate and alcohol, which are utilized as major sources of carbon and phosphate. In contrast, two novel mammalian GP-PDEs, GDE1/MIR16 and GDE3, were recently identified, and were shown to be involved in several physiological functions. GDE1/MIR16 was identified as a membrane protein interacting with RGS16, a regulator of G protein signaling, and found to hydrolyze glycerophosphoinositol preferentially. We have found that expression of GDE3 is significantly up-regulated during osteoblast differentiation and is involved in morphological changes of cells. Furthermore, five mammalian GP-PDEs were virtually identified, and very recent studies indicate that retinoic acid-induced expression of GDE2 plays essential roles in neuronal differentiation and neurite outgrowth. Thus mammalian GP-PDEs are likely to be important in controlling numerous cellular events, indicating that the GP-PDE superfamily in mammals might be a pharmacological target in the future.
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