WWW.JNEUROSCI.ORG
-
The Journal of Neuroscience
QUICK SEARCH:   [advanced]


     
-


HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP
The Journal of Neuroscience, May 23, 2007, 27(21):5603-5614; doi:10.1523/JNEUROSCI.4552-06.2007

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Submit an eLetter
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yoong, L. F.
Right arrow Articles by Too, H.-P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yoong, L. F.
Right arrow Articles by Too, H.-P.

 Previous Article  |  Next Article 

Cellular/Molecular
Glial Cell Line-Derived Neurotrophic Factor and Neurturin Inhibit Neurite Outgrowth and Activate RhoA through GFR{alpha}2b, an Alternatively Spliced Isoform of GFR{alpha}2

Li Foong Yoong1 and Heng-Phon Too1,2

1Department of Biochemistry, National University of Singapore, Singapore 119260, and 2Molecular Engineering of Biological and Chemical System/Chemical Pharmaceutical Engineering, Singapore–Massachusetts Institute of Technology Alliance, Singapore 117576

Correspondence should be addressed to Dr. Heng-Phon Too, Department of Biochemistry, National University of Singapore, Lower Kent Ridge Road, Singapore 119260. Email: bchtoohp{at}nus.edu.sg

The glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) belong to a structurally related family of neurotrophic factors. NTN exerts its effect through a multicomponent receptor system consisting of the GDNF family receptor {alpha}2 (GFR{alpha}2), RET, and/or NCAM (neural cell adhesion molecule). GFR{alpha}2 is alternatively spliced into at least three isoforms (GFR{alpha}2a, GFR{alpha}2b, and GFR{alpha}2c). It is currently unknown whether these isoforms share similar functional and biochemical properties. Using highly specific and sensitive quantitative real-time PCR, these isoforms were found to be expressed at comparable levels in various regions of the human brain. When stimulated with GDNF and NTN, both GFR{alpha}2a and GFR{alpha}2c, but not GFR{alpha}2b, promoted neurite outgrowth in transfected Neuro2A cells. These isoforms showed ligand selectivity in MAPK (mitogen-activated protein kinase) [ERK1/2 (extracellular signal-regulated kinase 1/2)] and Akt signaling. In addition, the GFR{alpha}2 isoforms regulated different early-response genes when stimulated with GDNF or NTN. In coexpression studies, GFR{alpha}2b was found to inhibit ligand-induced neurite outgrowth by GFR{alpha}2a and GFR{alpha}2c. Stimulation of GFR{alpha}2b also inhibited the neurite outgrowth induced by GFR{alpha}1a, another member of the GFR{alpha}. Furthermore, activation of GFR{alpha}2b inhibited neurite outgrowth induced by retinoic acid and activated RhoA. Together, these data suggest a novel paradigm for the regulation of growth factor signaling and neurite outgrowth via an inhibitory splice variant of the receptor. Thus, depending on the expressions of specific GFR{alpha}2 receptor spliced isoforms, GDNF and NTN may promote or inhibit neurite outgrowth through the multicomponent receptor complex.

Key words: GDNF; NTN; GFR{alpha}2; RhoA; inhibitory splice isoforms; neuroblastoma

Received Oct. 20, 2006; revised April 11, 2007; accepted April 14, 2007.

Correspondence should be addressed to Dr. Heng-Phon Too, Department of Biochemistry, National University of Singapore, Lower Kent Ridge Road, Singapore 119260. Email: bchtoohp{at}nus.edu.sg






 -
-

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help
-
Copyright 2009 by Society for Neuroscience ONLINE ISSN: 1529-2401
-