Regulation of GDNF and its receptor components GFR-α1, -α2 and Ret during development and in the mature retino-collicular pathway

Kretz, Alexandra; Jacob, Archana M.; Tausch, Svetlana; Straten, Guido; Isenmann, Stefan

doi:10.1016/j.brainres.2006.01.131

Cited by 17 publications

(11 citation statements)

References 40 publications

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“…A 35 kDa band of glycosylated GDNF was detected in both the limbal and the corneal epithelia, while the 21 kDa band was only detected in the limbal epithelium. A 53 kDa GFRα-1 band15 was detected only in the limbal epithelium. Real-time PCR showed that the levels of GDNF and GFRα-1 mRNA transcripts were four- to 10-fold higher in the limbal than in the corneal epithelia (fig 3A1, Student t test, p<0.01).…”

Section: Resultsmentioning

confidence: 94%

“…The presence of GDNF and GFRα-1 in human corneal and limbal epithelial tissues was confirmed by western blot analysis (fig 2). The reported molecular weight of GDNF is 21 kDa 15 and its glycosylated, disulfide-bonded homodimer protein has been noted to be about 35 kDa 16. A 35 kDa band of glycosylated GDNF was detected in both the limbal and the corneal epithelia, while the 21 kDa band was only detected in the limbal epithelium.…”

Section: Resultsmentioning

confidence: 99%

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Expression of glial cell-derived neurotrophic factor and its receptor in the stem-cell-containing human limbal epithelium

Bian

et al. 2008

British Journal of Ophthalmology

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Aim-To evaluate the expression pattern of glial cell line-derived neurotrophic factor (GDNF) with its receptors GDNF family receptor alpha-1 (GFRα-1) and Ret in the human corneal and limbal tissues, as well as in the primary human limbal epithelial cultures (PHLEC).Methods-Expression of GDNF and its receptors, and the co-localisation with stem cell associated and differentiation markers were evaluated by immunofluorescent staining, western blot analysis and real-time PCR in the fresh human corneoscleral tissues, as well as in the PHLEC. Single cell colony-forming and wound-healing assays were also evaluated in PHLEC.Results-GDNF and GFRα-1 were found to be expressed by a subset of basal cells and colocalised with ATP-binding cassette, subfamily G (WHITE), member 2 (ABCG2) and p63, but not with cytokeratin 3 in the human limbal basal epithelium. In PHLEC, they were expressed by a small population of cells in the less differentiated stage. The GDNF and GFRα-1-positive subpopulations were enriched for the expression of ABCG2 and p63 (p<0.01). Recombinant human GDNF promoted the proliferation and wound healing of epithelial cells in the PHLEC. In contrast, Ret was abundantly located in the human corneal epithelium except for the basal cells of the limbal epithelium.Conclusion-These findings indicate that GDNF and GFRα-1 may represent a property for the phenotype of human corneal epithelial precursor cells. GDNF may signal independently of Ret through GFRα-1 in the stem cell-containing limbal epithelium.Glial cell line-derived neurotrophic factor (GDNF) is a member of the GDNF family of neurotrophic factors, which also includes neurturin, artemin and persephin. 1 GDNF exerts its effects through a multicomponent receptor system consisting of the GDNF family receptor alpha-1 (GFRα-1), Ret receptor tyrosine kinase (Ret) and neural cell adhesion molecule (NCAM).2 3 GDNF has been shown to support the growth, maintenance and differentiation of a wide variety of neuronal systems. In recent years, GDNF was identified as an essential growth factor maintaining mouse spermatogonial stem cells,4 and it was found to increase motility and survival of cultured mesenchymal stem cells and ameliorate Corneal epithelial homeostasis is governed by a small subpopulation of corneal epithelial SCs located in the basal layer of the limbus.6 -8 However, no direct method has been found to identify the corneal epithelial SCs to date because of the lack of a unique molecular marker. In recent years, the functional role and the possible signal-transduction pathways induced by GDNF in the corneal epithelium have been investigated.9 10 GDNF may play an important role in corneal regeneration and wound healing. In the present study, we evaluated the expression pattern of GDNF with its receptors in the human corneal and limbal epithelia, as well as in the primary limbal epithelial cell cultures (PHLEC), with the intention of exploring the potential role of GDNF in the human stem cell niche. MATERIALS AND METHODS Materials and reagentsProgenit...

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Expression of glial cell-derived neurotrophic factor and its receptor in the stem-cell-containing human limbal epithelium

Bian

et al. 2008

British Journal of Ophthalmology

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“…The cell-typespecific expression of these receptors has been unclear because the techniques and reagents used have led to conflicting results. For example, Ret, GFR␣1, and GFR␣2 have been variably detected in multiple cell types, including photoreceptors, inner retinal cells, and Müller glia (Jomary et al, 1999(Jomary et al, , 2004Harada et al, 2002;Karlsson et al, 2002;Koberle and Ball 2002;Rothermel et al, 2004;Kretz et al, 2006). Reporter molecules expressed from endogenous loci have been successfully used to recapitulate and study native gene expression.…”

Section: Ret Is Expressed By Horizontal Amacrine and Ganglion Cellsmentioning

confidence: 99%

“…To further understand the roles of GFLs and their receptors in the retina, a number of expression studies have been performed (Jomary et al, 1999;Harada et al, 2002;Karlsson et al, 2002;Koberle and Ball, 2002;Jomary et al, 2004;Rothermel et al, 2004;Kretz et al, 2006). However, because of discrepancies reported in expression patterns of these receptors, it has been difficult to predict their roles in retinal function.…”

Section: Introductionmentioning

confidence: 99%

Neurturin-Mediated Ret Activation Is Required for Retinal Function

Brantley¹,

Jain²,

Barr³

et al. 2008

J. Neurosci.

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The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) [GDNF, NRTN (neurturin), ARTN (artemin), and PSPN (persephin)] interact with GDNF family receptors (GFR␣s) and activate intracellular signaling through the Ret receptor tyrosine kinase. To characterize the role of Ret signaling in retinal activity, we examined Ret hypomorphic and Ret conditional mice using electroretinography. We found that aberrant Ret function resulted in markedly diminished scotopic and photopic responses. Using mice deficient in individual GFLs, we found that only NRTN deficiency led to reduced retinal activity. To determine the potential target cell type for NRTN, we examined the retinal expression of its coreceptors (GFR␣1 and GFR␣2) and Ret using mice expressing fluorescence reporter enhanced green fluorescent protein from their respective loci. We found robust GFR␣1 and Ret expression in horizontal, amacrine, and ganglion cells, whereas GFR␣2 expression was only detected in a subset of amacrine and ganglion cells. In contrast to previous studies, no expression of GFR␣1, GFR␣2, or Ret was detected in photoreceptors or Müller cells, suggesting that these cells are not directly affected by Ret. Finally, detailed morphologic analyses of retinas from NRTN-and Ret-deficient mice demonstrated a reduction in normal horizontal cell dendrites and axons, abnormal extensions of horizontal cell and bipolar cell processes into the outer nuclear layer, and mislocalized synaptic complexes. These anatomic abnormalities indicate a possible basis for the abnormal retinal activity in the Ret and NRTN mutant mice.

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“…It supports survival and regulates the differentiation of many peripheral neurons, including sympathetic, parasympathetic, sensory and enteric neurons [1][2][3]. GDNF exerts its effects through a multicomponent receptor complex that consists of c-Ret receptor tyrosine kinase (Ret) and glycosylphosphatidylinositol-anchored (GPIanchored) receptor (GFRa1), which is required for the ligand binding [4][5][6][7]. GDNF activates Ret and several downstream signalling pathways, which include pathways involving Ras/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI 3-K)/Akt [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid induces functional c-Ret tyrosine kinase in human neuroblastoma

Yamada

Nomura²,

Uebersax³

et al. 2007

NeuroReport

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After the treatment of human neuroblastoma SH-SY5Y cells with retinoic acid for 24 h, the expression of c-Ret receptor tyrosine kinase was greatly elevated. Treatment of SH-SY5Y cells with glial cell line-derived neurotrophic factor under serum-free conditions after incubation of cells with retinoic acid resulted in the phosphorylation of c-Ret receptor tyrosine kinase, with subsequent morphological changes that included formation of neurites and rounding of cell bodies within 24-48 h. The number of neurite-bearing cells decreased with increasing concentrations of mitogen-activated protein kinase-specific and phosphatidylinositol 3-kinase inhibitors. These observations suggest that retinoic acid induces the expression of glial cell line-derived neurotrophic factor-responsive c-Ret receptor tyrosine kinase and that a glial cell line-derived neurotrophic factor-c-Ret receptor tyrosine kinase-induced signal transduction system that might be involved in neurite outgrowth via pathways that include phosphatidylinositol 3-kinase and mitogen-activated protein kinase.

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Regulation of GDNF and its receptor components GFR-α1, -α2 and Ret during development and in the mature retino-collicular pathway

Cited by 17 publications

References 40 publications

Expression of glial cell-derived neurotrophic factor and its receptor in the stem-cell-containing human limbal epithelium

Expression of glial cell-derived neurotrophic factor and its receptor in the stem-cell-containing human limbal epithelium

Neurturin-Mediated Ret Activation Is Required for Retinal Function

Retinoic acid induces functional c-Ret tyrosine kinase in human neuroblastoma

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