Leptin increases axonal growth cone size in developing mouse cortical neurons by convergent signals inactivating glycogen synthase kinase-3beta
Articolo
Data di Pubblicazione:
2006
Citazione:
Leptin increases axonal growth cone size in developing mouse cortical neurons by convergent signals inactivating glycogen synthase kinase-3beta / A. Valerio, V. Ghisi, M. Dossena, C. Tonello, A. Giordano, A. Frontini, M. Ferrario, M. Pizzi, P. Spano, M.O. Carruba, E. Nisoli. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 281:18(2006 May 05), pp. 12950-12958. [10.1074/jbc.M508691200]
Abstract:
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-3beta (GSK3beta), an event inactivating this kinase.
Leptin-mediated GSK3beta 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
Lepr(db/db) mice lacking functional leptin receptors; it was associated with
localized Ser-9-GSK3beta phosphorylation and mimicked by the GSK3beta inhibitor
SB216763. At concentrations preventing GSK3beta 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 GSK3beta
activity.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
A. Valerio, V. Ghisi, M. Dossena, C. Tonello, A. Giordano, A. Frontini, M. Ferrario, M. Pizzi, P. Spano, M.O. Carruba, E. Nisoli
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