Selective Agenesis of Mesencephalic Dopaminergic Neurons in Nurr1-Deficient Mice

Le, Weidong; Conneely, Orla M.; Zou, Linglong; He, Yi; Saucedo‐Cárdenas, Odila; Jankovic, Joseph; Mosier, Dennis R.; Appel, Stanley H.

doi:10.1006/exnr.1999.7191

Cited by 128 publications

(88 citation statements)

References 20 publications

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“…1), which is consistent with Nurr1 mRNA expression (Saucedo-Cardenas et al, 1998). The newborn Nurr1ϩ/Ϫ mice have decreased TH expression in SN and ventral tegmental area and significantly lower levels of DA in striatum (Zetterstrom et al, 1997;Le et al, 1998;SaucedoCardenas et al, 1998). When Nurr1ϩ/Ϫ mice enter adulthood, the striatal DA levels and nigral TH expression regain and reach to normal range in 1 month after birth, indicating the presence of compensatory mechanisms to maintain normal DAergic function in mature Nurr1ϩ/Ϫ mice.…”

Section: Discussionsupporting

confidence: 55%

“…The Nurr1 gene is of interest because Nurr1 knockout mice have selective and complete agenesis of SN and ventral tegmental area DAergic neurons (Zetterstrom et al, 1997;Le et al, 1998;Saucedo-Cardenas et al, 1998). The human Nurr1 (NOT) gene has been mapped to chromosome 2p22-23 (Magest et al, 1994), and its sequence has recently been identified (Ichinose et al, 1999;Tori et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Reduced Nurrl Expression Increases the Vulnerability of Mesencephalic Dopamine Neurons to MPTP‐Induced Injury

Conneely

et al. 1999

Journal of Neurochemistry

152

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Mutation in the Nurr1 gene, a member of the nuclear receptor superfamily, causes selective agenesis of dopaminergic neurons in the midbrain of null mice. Homozygous Nurr1 knockout mice (Nurr1Ϫ/Ϫ) die 1 day after birth, but heterozygous mice (Nurr1ϩ/Ϫ) survive postnatally without obvious locomotor deficits. Although adult Nurr1ϩ/Ϫ mice show significantly reduced Nurr1 protein levels in the substantia nigra (SN), they display a normal range of tyrosine hydroxylase-positive neuron numbers in the SN and normal levels of dopamine in the striatum. The reduction in Nurr1 expression in Nurr1ϩ/Ϫ mice, however, confers increased vulnerability to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) compared with wild-type (Nurr1ϩ/ϩ) mice. This study suggests that Nurr1 may play an important role in maintaining mature mesencephalic dopaminergic neuron function and that a defect in Nurr1 may increase susceptibility to SN injury. Key Words: Nurr1-Knockout mice-Dopaminergic neurons-Mesencephalon-1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Parkinson's disease.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Reduced Nurrl Expression Increases the Vulnerability of Mesencephalic Dopamine Neurons to MPTP‐Induced Injury

Conneely

et al. 1999

Journal of Neurochemistry

152

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“…For example, Nurr1, a member of the Nurr1/Nur77/Nor1 subfamily of receptors, appears to be essential for the migration, differentiation, and survival of dopaminergic neurons of the ventral mesencephon (Zetterstrom et al, 1997;Saucedo-Cardenas et al, 1998;Le et al, 1999;Wallen et al, 1999). Similarly, the orphan nuclear receptor RORα is crucial for maturation and survival of Purkinje cells in the cerebellum (Dussault et al, 1998;Chu and Zingg, 1999;Vogel et al, 2000).…”

Section: Orphan Nuclear Receptors In Cns Developmentmentioning

confidence: 99%

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

Tran

Lee

Marı́n

et al. 2003

Molecular and Cellular Neuroscience

101

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The ventromedial hypothalamic nucleus (VMN) is known to mediate autonomic responses in feeding and reproductive behaviors. To date, the most definitive molecular marker for the VMN is the orphan nuclear receptor steroidogenic factor-1 (SF-1). However, it is unclear whether SF-1 functions in the VMN as it does in peripheral endocrine organ development where loss of SF-1 results in organ agenesis due to apoptosis. Here, we provide evidence that SF-1 has a distinct role in later stages of VMN development by demonstrating the persistence of VMN precursors, the misexpression of an early marker (NKX2-1) concomitant with the absence of a late marker (BDNF neurotrophin), and the complete loss of projections to the bed nucleus of stria terminalis and the amygdala in sf-1 null mice. Our findings demonstrate that SF-1 is required for terminal differentiation of the VMN and suggest that transcriptional targets of SF-1 mediate normal circuitry between the hypothalamus and limbic structures in the telencephalon.

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“…In the brain, Pitx3 mRNA localizes specifically to the SN and VTA (14). A reduction in Pitx3 mRNA levels is observed in the ventral midbrain of Lmx1b knockout mice, 6-hydroxydopamine-lesioned rats, and Parkinson's patients (8,11,12,14). Yet, Pitx3 expression is maintained in the ventral midbrain of Nurr1 null mutant embryos (12).…”

mentioning

confidence: 99%

“…One of these, the orphan nuclear hormone receptor Nurr1, is required for maturation of mesDA neuron precursors. Mice harboring null alleles of Nurr1 do not express tyrosine hydroxylase (TH), which catalyzes the initial step of dopamine neurotransmitter biosynthesis (5)(6)(7)(8)(9)(10)(11). The other factor, LIM homeodomain transcription factor Lmx1b, contributes partially to the specification of mesDA neuronal progenitors beginning on embryonic day 12.5 in the mouse but is not essential for TH gene expression (12).…”

mentioning

confidence: 99%

Pitx3 is required for development of substantia nigra dopaminergic neurons

Nunes

Tovmasian

Silva

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

348

271

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Dopaminergic (DA) neurons of substantia nigra in the midbrain control voluntary movement, and their degeneration is the cause of Parkinson's disease. The complete set of genes required to specifically determine the development of midbrain DA subgroups is not known yet. We report here that mice lacking the bicoidrelated homeoprotein Pitx3 fail to develop DA neurons of the substantia nigra. Other mesencephalic DA neurons of the ventral tegmental area and retrorubral field are unaltered in their dopamine expression and histological organization. These data suggest that Pitx3-dependent gene expression is specifically required for the differentiation of DA progenitors within the mesencephalic DA system. M idbrain dopaminergic (DA) cells contribute to the control of voluntary movement, cognition, and emotional behavior. Degeneration of these cells results in Parkinson's disease, and aberrant dopamine neurotransmitter signaling is implicated in schizophrenia and addictive behavioral disorders (1-3). Within the midbrain there are three subgroups of DA neurons, the ventral tegmental area (VTA͞A10), substantia nigra (SN͞ A9), and retrorubral field (RRF͞A8), that together constitute the mesencephalic (mes) system (4). Those DA cells in the SN that innervate the striatum preferentially degenerate in Parkinson's disease, whereas other DA subgroups regulate emotional and reward behaviors.Transcription factors regulate the differentiation of midbrain DA neuron precursors. Two transcription factors have been shown to contribute to different aspects of mesDA neuronal differentiation. One of these, the orphan nuclear hormone receptor Nurr1, is required for maturation of mesDA neuron precursors. Mice harboring null alleles of Nurr1 do not express tyrosine hydroxylase (TH), which catalyzes the initial step of dopamine neurotransmitter biosynthesis (5-11). The other factor, LIM homeodomain transcription factor Lmx1b, contributes partially to the specification of mesDA neuronal progenitors beginning on embryonic day 12.5 in the mouse but is not essential for TH gene expression (12).A third transcription factor, the bicoid-related homeodomain-containing transcription factor Pitx3, which is also known as Ptx3, has been implicated in the development of DA neurons. Pitx3 gene expression is restricted to the developing eye and DA progenitor cells from embryonic day 11 throughout adult life in mice (13,14). In the brain, Pitx3 mRNA localizes specifically to the SN and VTA (14). A reduction in Pitx3 mRNA levels is observed in the ventral midbrain of Lmx1b knockout mice, 6-hydroxydopamine-lesioned rats, and Parkinson's patients (8,11,12,14). Yet, Pitx3 expression is maintained in the ventral midbrain of Nurr1 null mutant embryos (12). These data have been interpreted to suggest that Pitx3 contributes to the combinatorial code defined by multiple transcription factors that establish specification and differentiation of midbrain DA progenitors (12). Here we report that Pitx3 is essential for the development of neurons specific to the SN. The D...

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Selective Agenesis of Mesencephalic Dopaminergic Neurons in Nurr1-Deficient Mice

Cited by 128 publications

References 20 publications

Reduced Nurrl Expression Increases the Vulnerability of Mesencephalic Dopamine Neurons to MPTP‐Induced Injury

Reduced Nurrl Expression Increases the Vulnerability of Mesencephalic Dopamine Neurons to MPTP‐Induced Injury

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

Pitx3 is required for development of substantia nigra dopaminergic neurons

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