The novel protein MANI modulates neurogenesis and neurite-cone growth.
Neuronal regeneration and axonal re-growth in the injured mammalian central nervous system remains an unsolved field. 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]. In the present study we describe the novel protein MANI (myelin-associated neurite-outgrowth inhibitor) that localizes to neural membranes. Functional characterization of MANI overexpressing neural stem cells (NSCs) revealed that the protein promotes differentiation into catecholaminergic neurons. Yeast two-hybrid screening and co-immunoprecipitation experiments confirmed the cell division cycle protein 27 (Cdc27) as an interacting partner of Mani. The analyses of Mani-overexpressing PC12 cells demonstrated that Mani retards neuronal axonal growth as a positive effector of Cdc27 expression and activity. 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.
Mesh Terms:
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome, Blotting, Western, Brain, Cell Cycle Proteins, Cell Line, Tumor, Female, Gene Expression, Growth Cones, HeLa Cells, Humans, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Neural Stem Cells, Neurites, Neurogenesis, PC12 Cells, Parkinson Disease, Protein Binding, RNA Interference, Rats, Reverse Transcriptase Polymerase Chain Reaction
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome, Blotting, Western, Brain, Cell Cycle Proteins, Cell Line, Tumor, Female, Gene Expression, Growth Cones, HeLa Cells, Humans, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Neural Stem Cells, Neurites, Neurogenesis, PC12 Cells, Parkinson Disease, Protein Binding, RNA Interference, Rats, Reverse Transcriptase Polymerase Chain Reaction
J. Cell. Mol. Med.
Date: Aug. 01, 2011
PubMed ID: 20716133
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