Regenerating Islet-derived 1α (Reg-1α) Protein Is New Neuronal Secreted Factor That Stimulates Neurite Outgrowth via Exostosin Tumor-like 3 (EXTL3) Receptor

Regenerating islet-derived 1α (Reg-1α)/lithostathine, a member of a family of secreted proteins containing a C-type lectin domain, is expressed in various organs and plays a role in proliferation, differentiation, inflammation, and carcinogenesis of cells of the digestive system. We previously repor...

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Published in:The Journal of biological chemistry 2012-02, Vol.287 (7), p.4726-4739
Main Authors: Acquatella-Tran Van Ba, Isabelle, Marchal, Stéphane, François, Florence, Silhol, Michèle, Lleres, Coline, Michel, Bernard, Benyamin, Yves, Verdier, Jean-Michel, Trousse, Françoise, Marcilhac, Anne
Format: Article
Language:English
Subjects:
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Animals
Biochemistry
Cell Biology
Cell Culture
Cell Differentiation
Cell Membrane - genetics
Cell Membrane - metabolism
Cell Nucleus - genetics
Cell Nucleus - metabolism
Cellular Biology
EXTL3
Humans
Immunochemistry
Lithostathine - genetics
Lithostathine - metabolism
Lithostathine - pharmacology
Mice
N-Acetylglucosaminyltransferases - genetics
N-Acetylglucosaminyltransferases - metabolism
Nerve Tissue Proteins - immunology
Nerve Tissue Proteins - metabolism
Nerve Tissue Proteins - pharmacology
Neurites - metabolism
Neurobiology
PC12 Cells
Rat
Rats
Rats, Sprague-Dawley
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Recombinant Proteins - pharmacology
Reg-1α
siRNA
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Summary:Regenerating islet-derived 1α (Reg-1α)/lithostathine, a member of a family of secreted proteins containing a C-type lectin domain, is expressed in various organs and plays a role in proliferation, differentiation, inflammation, and carcinogenesis of cells of the digestive system. We previously reported that Reg-1α is overexpressed during the very early stages of Alzheimer disease, and Reg-1α deposits were detected in the brain of patients with Alzheimer disease. However, the physiological function of Reg-1α in neural cells remains unknown. Here, we show that Reg-1α is expressed in neuronal cell lines (PC12 and Neuro-2a) and in rat primary hippocampal neurons (E17.5). Reg-1α is mainly localized around the nucleus and at the membrane of cell bodies and neurites. Transient overexpression of Reg-1α or addition of recombinant Reg-1α significantly increases the number of cells with longer neurites by stimulating neurite outgrowth. These effects are abolished upon down-regulation of Reg-1α by siRNA and following inhibition of secreted Reg-1α by antibodies. Moreover, Reg-1α colocalizes with exostosin tumor-like 3 (EXTL3), its putative receptor, at the membrane of these cells. Overexpression of EXTL3 increases the effect of recombinant Reg-1α on neurite outgrowth, and Reg-1α is not effective when EXTL3 overexpression is down-regulated by shRNA. Our findings indicate that Reg-1α regulates neurite outgrowth and suggest that this effect is mediated by its receptor EXTL3. Background: Reg-1α is a small secretory protein overexpressed during the early stages of Alzheimer disease. Results: Secreted Reg-1α stimulates axon outgrowth, and this paracrine effect is mediated by its receptor EXTL3. Conclusion: Reg-1α emerges as an important actor in brain plasticity and the regenerative process. Significance: Learning how Reg-1α regulates the nerve cells is important for understanding its implications in early stages of Alzheimer disease.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.260349