The novel protein MANI modulates neurogenesis and neurite-cone growth.
Bottom Line: To date, three myelin-associated proteins [Nogo or reticulon 4 (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG)] are known to inhibit axonal regeneration via activation of the neuronal glycosylphosphatidylinositol-anchored Nogo receptor [NgR, together with p75 neurotrophin receptor (p75NTR) and Lingo-1].We show that knockdown of Cdc27, a component of the anaphase-promoting complex (APC), leads to enhanced neurite outgrowth.Our finding describes the novel MANI-Cdc27-APC pathway as an important cascade that prevents neurons from extending axons, thus providing implications for the potential treatment of neurodegenerative diseases.
Affiliation: Department of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, Singapore.Show MeSH
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Mentions: We next investigated the subcellular localization of Mani to obtain more information about its distribution and site of activity in the cell. Mani was particularly localized to neuronal cell membranes in the mouse brain hippocampus, sn and cortex tissue (Figs 4 and S5), with a specific co-distribution with Th+ neurons as assessed by IHC. Figure 4 demonstrates a similar staining pattern of Mani and Mtap2 in the cortex and the CA1, CA2, CA3 and dentate gyrus formation of the hippocampus suggesting its presence on the membrane of neuronal cell bodies and axonal fibres. We also performed IHC of Mani and Mapt substantiating the presence of Mani in neuronal axons (data not shown). Next, to answer if Mani localizes to oligoglial cells, we performed a co-staining of Mani and myelin basic protein (Mbp) and found its presence in neuronal axons but not oligodendrocytes (Figs 3 and S5). A further detailed IHC study demonstrated neural localization of Mani within the periaqueductal grey (PAG)–substantia gelatinosa (SG) pathway (Figs S6 and S7). To provide additional evidence about the membrane association of Mani, we performed a subcellular protein fractionation and found that Mani falls mainly within the membrane fraction obtained from PC12 cells (Fig. S8).
Affiliation: Department of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, Singapore.