title: Modulation of inositol polyphosphate levels regulates neuronal differentiation.
abstract: The binding of neurotrophins to tropomyosin receptor kinase receptors initiates several signaling pathways, including the activation of phospholipase C-γ, which promotes the release of diacylglycerol and inositol 1,4,5-trisphosphate (IP(3)). In addition to recycling back to inositol, IP(3) serves as a precursor for the synthesis of higher phosphorylated inositols, such as inositol 1,3,4,5,6-pentakisphosphate (IP(5)) and inositol hexakisphosphate (IP(6)). Previous studies on the effect of neurotrophins on inositol signaling were limited to the analysis of IP(3) and its dephosphorylation products. Here we demonstrate that nerve growth factor (NGF) regulates the levels of IP(5) and IP(6) during PC12 differentiation. Furthermore, both NGF and brain-derived neurotrophic factor alter IP(5) and IP(6) intracellular ratio in differentiated PC12 cells and primary neurons. Neurotrophins specifically regulate the expression of IP(5)-2 kinase (IP(5)-2K), which phosphorylates IP(5) into IP(6). IP(5)-2K is rapidly induced after NGF treatment, but its transcriptional levels sharply decrease in fully differentiated PC12 cells. Reduction of IP(5)-2K protein levels by small interfering RNA has an effect on the early stages of PC12 cell differentiation, whereas fully differentiated cells are not affected. Conversely, perturbation of IP(5)-2K levels by overexpression suggests that both differentiated PC12 cells and sympathetic neurons require low levels of the enzyme for survival. Therefore maintaining appropriate intracellular levels of inositol polyphosphates is necessary for neuronal survival and differentiation.
authors.affiliation: Cell Biology Unit and Laboratory for Molecular Cell Biology, Medical Research Council, University College London, London WC1E 6BT, United Kingdom Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom Department of Neuroscience, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Omar
authors.initials: O
authors.lastname: Loss
authors.forename: Chun Ting
authors.initials: CT
authors.lastname: Wu
authors.forename: Antonella
authors.initials: A
authors.lastname: Riccio
authors.forename: Adolfo
authors.initials: A
authors.lastname: Saiardi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016716:PC12 Cells; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D010833:Phytic Acid / Q000378:metabolism; D051381:Rats; D013564:Sympathetic Nervous System / Q000166:cytology
chemical_list: D007295:Inositol Phosphates; D009414:Nerve Growth Factors; C013571:inositol pentaphosphate; D010833:Phytic Acid; D015544:Inositol 1,4,5-Trisphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); D053148:Caspase 3