Expression of GFRα1 receptor splicing variants with different biochemical properties is modulated during kidney development

Charlet‐Berguerand, Nicolas; Hir, Hervé Le; Incoronato, Mariarosaria; Porzio, Umberto di; Yu, Yanbin; Jing, Shuqian; Franciscis, Vittorio de; Thermes, Claude

doi:10.1016/j.cellsig.2004.05.006

Cited by 10 publications

(7 citation statements)

References 35 publications

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“…Similarly, alternative spliced isoforms of the coreceptors RET (Lorenzo et al, 1997;de Graaff et al, 2001;Lee et al, 2002) and NCAM (Povlsen et al, 2003;Buttner et al, 2004) have been reported. The alternatively spliced isoforms of GFR␣1 have recently been shown to exhibit distinct biochemical functions (Charlet-Berguerand et al, 2004;Yoong et al, 2005). These observations are consistent with the emerging view that the combinatorial interactions of the spliced isoforms of GFR␣, RET, and NCAM may contribute to the multicomponent signaling system to produce the myriad of observed biological responses.…”

Section: Introductionsupporting

confidence: 74%

“…Both GDNF and NTN have previously been shown to have similar properties in activating the multicomponent receptor complex (Baloh et al, 1997;Airaksinen et al, 1999;Wang et al, 2000;Scott and Ibanez, 2001;Coulpier et al, 2002;Charlet-Berguerand et al, 2004). In addition, midbrain dopaminergic neurons that only express GFR␣1 appear to survive equally well with both GDNF and NTN in vitro and in vivo (Horger et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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Glial Cell Line-Derived Neurotrophic Factor and Neurturin Inhibit Neurite Outgrowth and Activate RhoA through GFRα2b, an Alternatively Spliced Isoform of GFRα2

Yoong¹,

Too²

2007

J. Neurosci.

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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 ␣2 (GFR␣2), RET, and/or NCAM (neural cell adhesion molecule). GFR␣2 is alternatively spliced into at least three isoforms (GFR␣2a, GFR␣2b, and GFR␣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␣2a and GFR␣2c, but not GFR␣2b, promoted neurite outgrowth in transfected Neuro2A cells. These isoforms showed ligand selectivity in MAPK (mitogen-activated protein kinase) [ERK1/2 (extracellular signalregulated kinase 1/2)] and Akt signaling. In addition, the GFR␣2 isoforms regulated different early-response genes when stimulated with GDNF or NTN. In coexpression studies, GFR␣2b was found to inhibit ligand-induced neurite outgrowth by GFR␣2a and GFR␣2c. Stimulation of GFR␣2b also inhibited the neurite outgrowth induced by GFR␣1a, another member of the GFR␣. Furthermore, activation of GFR␣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␣2 receptor spliced isoforms, GDNF and NTN may promote or inhibit neurite outgrowth through the multicomponent receptor complex.

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Section: Introductionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Glial Cell Line-Derived Neurotrophic Factor and Neurturin Inhibit Neurite Outgrowth and Activate RhoA through GFRα2b, an Alternatively Spliced Isoform of GFRα2

Yoong¹,

Too²

2007

J. Neurosci.

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“…At low ligand concentrations, GFRa1b mediated RET (co-receptor) phosphorylation to a larger extent than GFRa1a. 23 When transfected Neuro2A expressing both NCAM and RET endogenously were stimulated with either GDNF or NRTN, both GFRa1a and GFRa1b induced the phosphorylation of ERK1/2 In our study, RET9 is the predominant spliced co-receptor isoform in all human glioma samples and glioblastoma cell lines. The glioblastoma cell lines and samples had overexpression of GFRa1b.…”

Section: Discussionmentioning

confidence: 89%

Glial cell-line derived neurotrophic factor (GDNF) family of ligands confer chemoresistance in a ligand-specific fashion in malignant gliomas

Wan

Peng

et al. 2009

Journal of Clinical Neuroscience

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“…Few studies have examined the role of isoform-specific GFRα1 signalling, but evidence suggests that GFRα1a and GFRα1b elicit different downstream effects and have opposing roles in certain aspects of structural plasticity. 34 , 35 Although GFRα1a has been shown to enhance neurite outgrowth in stably transfected neuro2D cells exposed to GDNF, co-transfection with GFRα1b inhibits this process. 35 These findings suggest that reduced expression of GFRA1-L/GFRα1a in the human BLA may be associated with, or even contribute to, reductions in neuroplasticity.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression

et al. 2015

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Although multiple studies have reported that peripheral glial cell line-derived neurotrophic factor (GDNF) is reduced in depression, cerebral GDNF signalling has yet to be examined in this condition. Here, we report an isoform-specific decrease in GDNF family receptor alpha 1 (GFRA1) mRNA expression, resulting in lowered GFRα1a protein levels in basolateral amygdala (BLA) samples from depressed subjects. Downregulation of GFRα1a was associated with increased expression of microRNAs, including miR-511, predicted to bind to long 3' untranslated region (3'-UTR)-containing transcripts (GFRA1-L) coding for GFRα1a. Transfection of human neural progenitor cells (NPCs) with a miR-511 mimic was sufficient to repress GFRA1-L/GFRα1a without altering GFRα1b, and resulted in pathway-specific changes in immediate early gene activity. Unexpectedly, GFRα1a knockdown did not reduce NPC responses to GDNF. Rather, it greatly enhanced mitogen-activated protein kinase signalling. This effect appeared to be mediated by GDNF/soluble GFRα1/neural cell adhesion molecule binding, and substituting the soluble GFRα1a/GFRα1b content of miR-511-transfected NPCs with that of controls rescued signalling. In light of previous reports suggesting that GFRα1b can inhibit GFRα1a-induced neuroplasticity, we also assessed the association between GFRα1 and doublecortin (DCX; a hyperplastic marker) in human BLA. Although controls displayed coordinated expression of GFRα1a and b isoforms and these correlated positively with DCX, the only significant association observed among depressed subjects was a strongly negative correlation between GFRα1b and DCX. Taken together, these results suggest that microRNA-mediated reductions of GFRα1a in depression change the quality, rather than the quantity, of GDNF signalling. They also suggest that central GDNF signalling may represent a novel target for antidepressant treatment.

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Expression of GFRα1 receptor splicing variants with different biochemical properties is modulated during kidney development

Cited by 10 publications

References 35 publications

Glial Cell Line-Derived Neurotrophic Factor and Neurturin Inhibit Neurite Outgrowth and Activate RhoA through GFRα2b, an Alternatively Spliced Isoform of GFRα2

Glial Cell Line-Derived Neurotrophic Factor and Neurturin Inhibit Neurite Outgrowth and Activate RhoA through GFRα2b, an Alternatively Spliced Isoform of GFRα2

Glial cell-line derived neurotrophic factor (GDNF) family of ligands confer chemoresistance in a ligand-specific fashion in malignant gliomas

MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression

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