GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo

Arenas, Ernest; Trupp, Miles; Åkerud, Peter; Ibáñez, Carlos F.

doi:10.1016/0896-6273(95)90024-1

Cited by 329 publications

(208 citation statements)

References 45 publications

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“…NT-4/5 prevents atrophy of rat rubrospinal neurons after axotomy and promotes rubrospinal regeneration (Kobayashi et al, 1997). GDNF promotes survival and axonal regeneration of noradrenergic neurons of the locus coeruleus (Arenas et al, 1995;Holm et al 2002). In addition, OECs produce molecules known to be involved in neurite extension such as L1, laminin, N-CAM, PSA-N-CAM, and fibronectin (Ramón-Cueto and Avila, 1998).…”

Section: Discussionmentioning

confidence: 99%

Olfactory ensheathing cells transplanted in lesioned spinal cord prevent loss of spinal cord parenchyma and promote functional recovery

Verdú

García-Alías

Forés

et al. 2003

Glia

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We studied the effects of olfactory ensheathing cells (OECs) transplanted in a photochemical spinal cord injury in adult rats. After dorsal laminectomy at T8 vertebra, subjacent spinal cord was bathed with rose Bengal for 10 min and illuminated with visible light by means of an optic fiber connected to a halogen lamp for 2.5 min at maximal intensity of 8 kLux. Eight injured rats received a suspension of OECs in DMEM, and another eight rats received DMEM alone. Locomotor ability scored by the BBB scale, pain sensibility by the plantar algesimetry test, and motor-and somatosensory-evoked potentials by electrophysiological techniques were evaluated for 3 months postsurgery. Finally, all rats were perfused with paraformaldehyde and transverse sections from the spinal cord segment at the lesion site were immunostained against GFAP. Area of the preserved spinal cord parenchyma was measured from the GFAPimmunolabeled cord sections. The BBB score and the amplitude of motor-and somatosensory-evoked potentials were higher in OECs-transplanted rats than in DMEMinjected animals throughout follow-up, whereas the withdrawal response to heat noxious stimulus was lower in OEC-than in DMEM-injected rats. The area of preserved spinal cord was significantly larger in OECs-transplanted rats than in DMEM-injected animals. These results indicate that OECs promote functional and morphological preservation of the spinal cord after photochemical injury. GLIA 42:275-286, 2003.

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Section: Discussionmentioning

confidence: 99%

Olfactory ensheathing cells transplanted in lesioned spinal cord prevent loss of spinal cord parenchyma and promote functional recovery

Verdú

García-Alías

Forés

et al. 2003

Glia

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“…GDNF protects dopaminergic nigrostriatal neurons from neurotoxins in rodents and primates, and induces fiber outgrowth when administered into the brain parenchyma (Tomac et al, 1995;Gash et al, 1996;Kordower et al, 2000). GDNF has also a neuroprotective effect on noradrenergic neurons of the rodent locus ceruleus (Arenas et al, 1995;Pascual et al, 2008). Based on these data, stimulation of endogenous GDNF production and/or exogenous GDNF administration are considered promising therapeutic strategies for Parkinson's disease (PD) (Kirik et al, 2004;Pascual et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

GDNF Is Predominantly Expressed in the PV+ Neostriatal Interneuronal Ensemble in Normal Mouse and after Injury of the Nigrostriatal Pathway

Hidalgo-Figueroa¹,

Bonilla²,

Gutiérrez³

et al. 2012

J. Neurosci.

104

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Glial cell line-derived neurotrophic factor (GDNF) is absolutely required for survival of dopaminergic (DA) nigrostriatal neurons and protect them from toxic insults. Hence, it is a promising, albeit experimental, therapy for Parkinson's disease (PD). However, the source of striatal GDNF is not well known. GDNF seems to be normally synthesized in neurons, but numerous reports suggest GDNF production in glial cells, particularly in the injured brain. We have studied in detail striatal GDNF production in normal mouse and after damage of DA neurons with MPTP. Striatal GDNF mRNA was present in neonates but markedly increased during the first 2-3 postnatal weeks. Cellular identification of GDNF by unequivocal histochemical methods demonstrated that in normal or injured adult animals GDNF is expressed by striatal neurons and is not synthesized in significant amounts by astrocytes or microglial cells. GDNF mRNA expression was not higher in reactive astrocytes than in normal ones. Approximately 95% of identified neostriatal GDNF-expressing cells in normal and injured animals are parvalbumin-positive (PVϩ) interneurons, which only represent ϳ0.7% of all striatal neurons. The remaining 5% of GDNFϩ cells are cholinergic and somatostatinϩ interneurons. Surprisingly, medium spiny projection neurons (MSNs), the vast majority of striatal neurons that receive a strong DA innervation, do not express GDNF. PVϩ interneurons constitute an oscillatory functional ensemble of electrically connected cells that control MSNs' firing. Production of GDNF in the PVϩ neurons might be advantageous to supply synchronous activity-dependent release of GDNF in broad areas of the striatum. Stimulation of the GDNF-producing striatal PVϩ ensemble in PD patients could have therapeutic effects.

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“…The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) constitute a family of four homologous neurotrophic factors that are vital to the development and maintenance of the nervous system and kidneys (Henderson et al, 1994;Arenas et al, 1995;Buj-Bello et al, 1995;Li et al, 1995;Mount et al, 1995;Oppenheim et al, 1995;Trupp et al, 1995;Moore et al, 1996;Pichel et al, 1996;Sánchez et al, 1996;Enomoto et al, 2000). The GFLs consist of GDNF, NRTN (neurturin), PSPN (persephin), and ARTN (artemin), all of which signal via a common receptor tyrosine kinase, Ret (Lin et al, 1993;Durbec et al, 1996;Kotzbauer et al, 1996;Treanor et al, 1996;Baloh et al, 1998b;Milbrandt et al, 1998;Rosenblad et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Tsui¹,

Pierchala

2008

J. Neurosci.

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The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are critical for nervous system development and maintenance. GFLs promote survival and growth via activation of the receptor tyrosine kinase (RTK) Ret. In sympathetic neurons, the duration of Ret signaling is governed by how rapidly Ret is degraded after its activation. In an effort to elucidate mechanisms that control the half-life of Ret, we have identified two novel Ret interactors, CD2-associated protein (CD2AP) and Cbl-3. CD2AP, an adaptor molecule involved in the internalization of ubiquitinated RTKs, is associated with Ret under basal, unstimulated conditions in neurons. After Ret activation by GDNF, CD2AP dissociates. Similarly, the E3-ligase Cbl-3 interacts with unphosphorylated Ret and dissociates from Ret after Ret activation. In contrast to their dissociation from autophosphorylated Ret, an interaction between CD2AP and Cbl-3 is induced by GDNF stimulation of sympathetic neurons, suggesting that CD2AP and Cbl-3 dissociate from Ret as a complex. In neurons, the overexpression of CD2AP enhances the degradation of Ret and inhibits GDNF-dependent survival, and gene silencing of CD2AP blocks Ret degradation and promotes GDNF-mediated survival. Surprisingly, Cbl-3 overexpression dramatically stabilizes activated Ret and enhances neuronal survival, even though Cbl-family E3 ligases normally function to trigger RTK downregulation. In combination with CD2AP, however, Cbl-3 promotes Ret degradation rapidly and almost completely blocks survival promotion by GDNF, suggesting that Cbl-3 acts as a switch that is triggered by CD2AP and oscillates between inhibition and promotion of Ret degradation. Consistent with the hypothesis, Cbl-3 silencing in neurons only inhibited Ret degradation and enhanced neuronal survival in combination with CD2AP silencing. CD2AP and Cbl-3, therefore, constitute a checkpoint that controls the extent of Ret downregulation and, thereby, the sensitivity of neurons to GFLs.

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GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo

Cited by 329 publications

References 45 publications

Olfactory ensheathing cells transplanted in lesioned spinal cord prevent loss of spinal cord parenchyma and promote functional recovery

Olfactory ensheathing cells transplanted in lesioned spinal cord prevent loss of spinal cord parenchyma and promote functional recovery

GDNF Is Predominantly Expressed in the PV+ Neostriatal Interneuronal Ensemble in Normal Mouse and after Injury of the Nigrostriatal Pathway

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

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