The GDNF family: Signalling, biological functions and therapeutic value

Airaksinen, Matti S.; Saarma, Märt

doi:10.1038/nrn812

Cited by 1,589 publications

(1,373 citation statements)

References 82 publications

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“…ARTN signaling is mediated through a multi-component receptor complex including the glycosylphosphatidylinositol-anchored GDNF family receptor a3 (GFRa3) or GFRa1 as one ligand binding component and RET receptor tyrosine kinase as one common signaling component (Airaksinen and Saarma, 2002;Carmillo et al, 2005). We have recently identified an oncogenic role of ARTN in mammary carcinoma (Kang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

et al. 2010

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We have previously identified an oncogenic role of artemin (ARTN), a member of glial cell derived neurotrophic factor family of ligands, in mammary carcinoma. We herein report that ARTN is an estrogen-inducible gene. Metaanalysis of gene expression data sets showed that ARTN expression is positively correlated to estrogen receptor (ER) status in human mammary carcinoma. Furthermore, in patients with ER-positive mammary carcinoma treated with tamoxifen, high ARTN expression is significantly correlated with decreased survival. Forced expression of ARTN in ER-positive human mammary carcinoma cells increased ER transcriptional activity, promoted estrogenindependent growth and produced resistance to tamoxifen and fulvestrant in vitro and to tamoxifen in xenograft models. ARTN-stimulated resistance to tamoxifen and fulvestrant is mediated by increased BCL-2 expression. Conversely, depletion of endogenous ARTN by smallinterfering RNA or functional antagonism of ARTN by antibody enhanced the efficacy of antiestrogens. Tamoxifen decreased ARTN expression in tamoxifen-sensitive mammary carcinoma cells whereas ARTN expression was increased in tamoxifen-resistant cells and not affected by tamoxifen treatment. Antibody inhibition of ARTN in tamoxifen-resistant cells improved tamoxifen sensitivity. Functional antagonism of ARTN therefore warrants consideration as an adjuvant therapy to enhance antiestrogen efficacy in ER-positive mammary carcinoma.

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Section: Introductionmentioning

confidence: 99%

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

et al. 2010

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“…GDNF has been a focus due to its potent effects on dopamine neurons, 1 although it has since been found to bind to receptors and exert trophic effects on a variety of neurons within the brain. 41 As PD attacks a range of neural transmitter systems in addition to dopamine, this pleotrophic aspect of GDNF may benefit multiple neurons, leading to enhanced effects in patients. However, delivery of GDNF has been a consistent challenge.…”

Section: Discussionmentioning

confidence: 99%

Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates

et al. 2005

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Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival and functioning of dopamine neurons in a variety of animal models and some recent human trials. However, delivery of any protein to the brain remains a challenge due to the blood/brain barrier. Here we show that human neural progenitor cells (hNPC) can be genetically modified to release glycosylated GDNF in vitro under an inducible promoter system. hNPC-GDNF were transplanted into the striatum of rats 10 days following a partial lesion of the dopamine system. At 2 weeks following transplantation, the cells had migrated within the striatum and were releasing physiologically relevant levels of GDNF. This was sufficient to increase host dopamine neuron survival and fiber outgrowth. At 5 weeks following grafting there was a strong trend towards functional improvement in transplanted animals and at 8 weeks the cells had migrated to fill most of the striatum and continued to release GDNF with transport to the substantia nigra. These cells could also survive and release GDNF 3 months following transplantation into the aged monkey brain. No tumors were found in any animal. hNPC can be genetically modified, and thereby represent a safe and powerful option for delivering growth factors to specific targets within the central nervous system for diseases such as Parkinson's.

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“…It signals through a multicomponent receptor complex comprising a glycosylphosphatidylinositol (GPI)-anchored cell surface molecule (Gdnf family receptor (Gfr) alpha-1, or Gfrα-1) and the Ret (rearranged during transfection) tyrosine kinase transmembrane protein (Jing et al, 1996;Treanor et al, 1996). The binding of Gdnf triggers the activation of multiple signaling pathways in responsive cells (Airaksinen and Saarma, 2002). As mentioned previously, Gdnf in the testis is produced by Sertoli cells, which establish the niche in which the SSCs reside (Viglietto et al, 2000;Meng et al, 2000;Meng et al, 2001a), and this activity extends throughout life (Chen et al, 2005).…”

Section: Role Of Gdnf In the Mammalian Testismentioning

confidence: 99%

Gdnf signaling pathways within the mammalian spermatogonial stem cell niche

Hofmann

2008

Molecular and Cellular Endocrinology

204

178

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SummaryMammalian spermatogenesis is a complex process in which male germ-line stem cells develop to ultimately form spermatozoa. Spermatogonial stem cells, or SSCs, are found in the basal compartment of the seminiferous epithelium. They self-renew to maintain the pool of stem cells throughout life, or they differentiate to generate a large number of germ cells. A balance between SSC self-renewal and differentiation in the adult testis is therefore essential to maintain normal spermatogenesis and fertility. Maintenance and self-renewal are tightly regulated by extrinsic signals from the surrounding microenvironment, called the spermatogonial stem cell niche. By physically supporting the SSCs and providing them with growth factors, the Sertoli cell is the main component of the niche. In addition, adhesion molecules that connect the SSCs to the basement membrane and cellular components of the interstitium between the seminiferous tubules are important regulators of the niche function. This review mainly focuses on glial cell line-derived neurotrophic factor (Gdnf), which is produced by Sertoli cells to maintain SSCs self-renewal, and the downstream signaling pathways induced by this crucial growth factor. Interactions between Gdnf and other signaling pathways that maintain self-renewal, as well as the role of novel SSC-and Sertoli cell-specific transcription factors, are also discussed.

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The GDNF family: Signalling, biological functions and therapeutic value

Cited by 1,589 publications

References 82 publications

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates

Gdnf signaling pathways within the mammalian spermatogonial stem cell niche

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