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

Nikolai Kholodilov, Olga Yarygina, Tinmarla Frances Oo, Hui Zhang, David Sulzer, William Dauer, Robert E. Burke

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3136-3146
Number of pages11
JournalJournal of Neuroscience
Volume24
Issue number12
DOIs
StatePublished - Mar 24 2004
Externally publishedYes

Fingerprint

Glial Cell Line-Derived Neurotrophic Factor
Dopaminergic Neurons
Substantia Nigra
Cell Death
Ventral Tegmental Area
Corpus Striatum
Amphetamine
Tetracycline
Neutralizing Antibodies
Parkinson Disease
Hippocampus
Apoptosis
Phenotype
Neurons
Injections
Wounds and Injuries

Keywords

  • Apoptosis
  • Neurotrophic factors
  • Parkinson's disease
  • Programmed cell death
  • Striatum
  • Substantia nigra

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets. / Kholodilov, Nikolai; Yarygina, Olga; Oo, Tinmarla Frances; Zhang, Hui; Sulzer, David; Dauer, William; Burke, Robert E.

In: Journal of Neuroscience, Vol. 24, No. 12, 24.03.2004, p. 3136-3146.

Research output: Contribution to journalArticle

Kholodilov, Nikolai ; Yarygina, Olga ; Oo, Tinmarla Frances ; Zhang, Hui ; Sulzer, David ; Dauer, William ; Burke, Robert E. / Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets. In: Journal of Neuroscience. 2004 ; Vol. 24, No. 12. pp. 3136-3146.
@article{dd78b5f3887740cdaf99bb3e1497dda6,
title = "Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets",
abstract = "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.",
keywords = "Apoptosis, Neurotrophic factors, Parkinson's disease, Programmed cell death, Striatum, Substantia nigra",
author = "Nikolai Kholodilov and Olga Yarygina and Oo, {Tinmarla Frances} and Hui Zhang and David Sulzer and William Dauer and Burke, {Robert E.}",
year = "2004",
month = "3",
day = "24",
doi = "10.1523/JNEUROSCI.4506-03.2004",
language = "English (US)",
volume = "24",
pages = "3136--3146",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "12",

}

TY - JOUR

T1 - Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

AU - Kholodilov, Nikolai

AU - Yarygina, Olga

AU - Oo, Tinmarla Frances

AU - Zhang, Hui

AU - Sulzer, David

AU - Dauer, William

AU - Burke, Robert E.

PY - 2004/3/24

Y1 - 2004/3/24

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Neurotrophic factors

KW - Parkinson's disease

KW - Programmed cell death

KW - Striatum

KW - Substantia nigra

UR - http://www.scopus.com/inward/record.url?scp=1642546572&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1642546572&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.4506-03.2004

DO - 10.1523/JNEUROSCI.4506-03.2004

M3 - Article

C2 - 15044553

AN - SCOPUS:1642546572

VL - 24

SP - 3136

EP - 3146

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 12

ER -