Regional and Cell-Specific Expression of GDNF in Rat Brain

Schaar, Dale; Sieber, Beth-Anne; Dreyfus, Cheryl F.; Black, Ira B.

doi:10.1006/exnr.1993.1207

Cited by 262 publications

(140 citation statements)

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“…This hypothesis is further supported by a number of previous observations. GDNF mRNA is highly expressed in the striatum during development (Schaar et al, 1993;Stromberg et al, 1993;Blum and Weickert, 1995;Choi-Lundberg and Bohn, 1995;Golden et al, 1999), and we have shown by quantitative analysis that its highest level of expression is on PND 2 (Cho et al, 2003), during the first phase. The receptor for GDNF, GDNF receptor ␣1 (GFR␣1), and its signaling tyrosine kinase, Ret, are both highly expressed in SNpc during development (Widenfalk et al, 1997;Yu et al, 1998).…”

Section: Discussionmentioning

confidence: 77%

“…We have evaluated the possibility that GDNF may serve as a physiological, limiting, target-derived factor for SN DA neurons. Its mRNA is present in striatum and expressed at high levels during early postnatal development (Schaar et al, 1993;Stromberg et al, 1993;Blum and Weickert, 1995;Choi-Lundberg and Bohn, 1995;Cho et al, 2003). We have shown that GDNF is able to support DA neurons by suppressing apoptosis in a postnatal primary culture model, established during the natural cell death period for these neurons (Burke et al, 1998).…”

Section: Introductionmentioning

confidence: 89%

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Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

Kholodilov¹,

Yarygina²,

Oo³

et al. 2004

J. Neurosci.

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Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore dopamine (DA) neurons in injury models and is being evaluated for the treatment of Parkinson's disease. Nevertheless, little is known of its physiological role. We have shown that GDNF suppresses apoptosis in DA neurons of the substantia nigra (SN) postnatally both in vitro and during their first phase of natural cell death in vivo. Furthermore, intrastriatal injection of neutralizing antibodies augments cell death, suggesting that endogenous GDNF plays a role as a target-derived factor. Such a role would predict that overexpression of GDNF in striatum would increase the surviving number of SN DA neurons. To test this hypothesis, we used the tetracycline-dependent transcription activator (tTA)/tTA-responsive promoter system to create mice that overexpress GDNF selectively in the striatum, cortex, and hippocampus. These mice demonstrate an increased number of SN DA neurons after the first phase of natural cell death. However, this increase does not persist into adulthood. As adults, these mice also do not have increased dopaminergic innervation of the striatum. They do, however, demonstrate increased numbers of ventral tegmental area (VTA) neurons and increased innervation of the cortex. This morphologic phenotype is associated with an increased locomotor response to amphetamine. We conclude that striatal GDNF is necessary and sufficient to regulate the number of SN DA neurons surviving the first phase of natural cell death, but it is not sufficient to increase their final adult number. GDNF in VTA targets, however, is sufficient to regulate the adult number of DA neurons.

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Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 89%

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

Kholodilov¹,

Yarygina²,

Oo³

et al. 2004

J. Neurosci.

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“…GDNF is highly expressed in the developing rat striatum, yet its concentration is relatively low in the adult brain (Choi-Lundberg and Bohn, 1995;Schaar et al, 1993;Stromberg et al, 1993). Several studies in the 6-hydroxydopamine (6-OHDA) lesioned striatum of rats have demonstrated improvements in survival and outgrowth of grafted fetal DA neurons when central injections of GDNF have been administered, or when GDNF overexpressing cells have been co-grafted to the striatum (Ahn et al, 2005;Espejo et al, 2000;Rosenblad et al, 1996;Sautter et al, 1998;Sinclair et al, 1996;Sullivan et al, 1998;Wilby et al, 1999;Yurek, 1998).…”

Section: Introductionmentioning

confidence: 99%

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

Elsworth

Redmond

Léránth

et al. 2008

Experimental Neurology

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Neural transplantation offers the potential of treating Parkinson's disease by grafting fetal dopamine neurons to depleted regions of the brain. However, clinical studies of neural grafting in Parkinson's disease have produced only modest improvements. One of the main reasons for this is the low survival rate of transplanted neurons. The inadequate supply of critical neurotrophic factors in the adult brain is likely to be a major cause of early cell death and restricted outgrowth of fetal grafts placed into the mature striatum. Glial derived neurotrophic factor (GDNF) is a potent neurotrophic factor that is crucial to the survival, outgrowth and maintenance of dopamine neurons, and so is a candidate for protecting grafted fetal dopamine neurons in the adult brain. We found that implantation of adenoassociated virus type 2 encoding GDNF (AAV2-GDNF) in the normal monkey caudate nucleus induced over-expression of GDNF that persisted for at least 6 months after injection. In a 6-month within-animal controlled study, AAV2-GDNF enhanced the survival of fetal dopamine neurons by 4-fold, and increased the outgrowth of grafted fetal dopamine neurons by almost 3-fold in the caudate nucleus of MPTP-treated monkeys, compared with control grafts in the other caudate nucleus. Thus, the addition of GDNF gene therapy to neural transplantation may be a useful strategy to improve treatment for Parkinson's disease.

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“…It has been reported that mesencephalic astrocytes may play a neuroprotective role in dopaminergic neuron cultures by secreting neurotrophic factors (Liu and Lauder, 1992;Poltorak et al, 1992;Alexi and Hefti, 1993;Giulian, 1993;Magal et al, 1993;Schaar et al, 1993). In contrast, glia may also contribute to neurotoxicity by metabolizing compounds to more toxic forms, as is the case for 1-methyl-4-phenyl-1 ‚2,3,6-tetrahydropyridine (MPTP) (Chiba et al, 1985;Marini et al, 1989;Di Monte et al, 1992) or by secreting neurotoxins directly as is the case of activated microglia (Piani et al, 1991;Chao et al, 1992;Banati et al, 1993;Giulian, 1993;Giulian et al, 1993;Lees, 1993).…”

mentioning

confidence: 99%

Lipopolysaccharide Intranigral Injection Induces Inflammatory Reaction and Damage in Nigrostriatal Dopaminergic System

Castaño

Herrera

Cano

et al. 1998

Journal of Neurochemistry

367

270

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Abstract:The pathogenesis of Parkinson's disease is still poorly understood. To address the hypothesis that immunemediated events, such as microglial activation, may be involved in the dopaminergic neurodegeneration, we have studied the effect that intranigral injection of the immunostimulant lipopolysaccharide has on monoaminergic neurotransmitters in rats. Activation of microglial cells, visualized by immunohistochemistry with a specific monoclonal antibody, was already obvious 2 days after injection. In relation to the biochemical parameters studied, we found a significant decrease of dopamine levels in both the substantia nigra and striatum up to at least 21 days after intranigral injection of lipopolysaccharide. This result was supported by the decrease in tyrosine hydroxylase activity and the loss of tyrosine hydroxylase-positive neuronal bodies, shown by immunohistochemistry. These alterations of the dopaminergic system did not reverse during the interval studied (21 days); conversely, the serotoninergic system suffered only transient damage. In addition, we found that the neurotoxic effect of lipopolysaccharide was not mediated by nitric oxide. Based on our results we suggest that the nigrostriatal dopaminergic system is susceptible to damage by inf lammatory events and that these may be implicated in neurodegeneration processes such as Parkinson's disease.

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Regional and Cell-Specific Expression of GDNF in Rat Brain

Cited by 262 publications

References 0 publications

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

Lipopolysaccharide Intranigral Injection Induces Inflammatory Reaction and Damage in Nigrostriatal Dopaminergic System

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