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J. Biol. Chem., Vol. 281, Issue 18, 12950-12958, May 5, 2006
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Leptin Increases Axonal Growth Cone Size in Developing Mouse Cortical Neurons by Convergent Signals Inactivating Glycogen Synthase Kinase-3
*
1
From the
Center for Study and Research on Obesity, Department of Pharmacology, School of Medicine, University of Milan, 20129 Milan, ||Department of Preclinical Sciences, University of Milan, 20157 Milan, ¶Division of Pharmacology, Department of Biomedical Sciences and Biotechnologies, University of Brescia, 25123 Brescia, **Institute of Normal Human Morphology, School of Medicine, Marche Polytechnic University, 60020 Ancona, and Istituto Auxologico Italiano, 20149 Milan, Italy
We examined the effects of the adipose hormone leptin on the development of mouse cortical neurons. Treatment of neonatal and adult mice with intraperitoneal leptin (5 mg/kg) induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in pyriform and entorhinal cortex neurons. Stimulation of cultured embryonic cortical neurons with leptin evoked Janus kinase 2 and ERK1/2 phosphorylation and activated the downstream effector 90-kDa ribosomal protein S6 kinase. Moreover, leptin elicited the phosphorylation of the phosphatidylinositol 3-kinase effector Akt and evoked Ser-9 phosphorylation of glycogen synthase kinase-3
(GSK3), an event inactivating this kinase. Leptin-mediated GSK3 phosphorylation was prevented by the MEK/ERK inhibitor PD98059, the phosphatidylinositol 3-kinase inhibitor LY294002, or the protein kinase C inhibitor GF109203X. Exposure of cortical neurons to leptin also induced Ser-41 phosphorylation of the neuronal growth-associated protein GAP-43, an effect prevented by LY294002 and GF109203X but not by PD98059. Ser-41-GAP-43 phosphorylation is usually high in expanding axonal growth cones. Neurons exposed to 100 ng/ml leptin for 72 h displayed reduced rate of growth cone collapse, a shift of growth cone size distribution toward higher values, and a 4-fold increase in mean growth cone surface area compared with control cultures. The leptin-induced growth cone spreading was hampered in cortical neurons from Leprdb/db mice lacking functional leptin receptors; it was associated with localized Ser-9-GSK3 phosphorylation and mimicked by the GSK3 inhibitor SB216763. At concentrations preventing GSK3 phosphorylation, PD98059, LY294002, or GF109203X reversed the leptin-induced growth cone surface enlargement. We concluded that the leptin-mediated regulation of growth cone morphogenesis in cortical neurons relies on upstream regulators of GSK3 activity.
Received for publication, August 8, 2005 , and in revised form, March 6, 2006.
* This work was supported by Ministero dell'Università e della Ricerca Grant 2003057593 (to E. N. and A. V.) and Ministero della Salute grant (to E. N. and M. O. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.
1 To whom correspondence should be addressed: Dept. of Pharmacology, University of Milan, via Vanvitelli 32, 20129 Milan, Italy. Tel.: 39-02-50317082; Fax: 39-02-50316949; E-mail: enzo.nisoli{at}unimi.it.
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