Orphan Nuclear Receptor Nurr1 Is Essential for Ret Expression in Midbrain Dopamine Neurons and in the Brain Stem

doi:10.1006/mcne.2001.1057

Molecular and Cellular Neuroscience

Volume 18, Issue 6, December 2001, Pages 649-663

https://doi.org/10.1006/mcne.2001.1057 Get rights and content

Abstract

The orphan nuclear receptor Nurr1 is essential for development of midbrain dopamine (DA) cells. In Nurr1-deficient mice, DA precursor cells fail to migrate normally, are unable to innervate target areas, and only transiently express DA cell marker genes. In the search for Nurr1-regulated genes that might explain this developmental phenotype, we found that expression of the receptor tyrosine kinase Ret is deregulated in these cells of Nurr1-deficient embryos. In addition, our analyses establish Nurr1 as an early marker for the dorsal motor nucleus (DMN) of the vagus nerve. Interestingly, Ret expression is absent also in these cells in Nurr1-targeted mice. Neuronal innervation of vagus nerve target areas appeared normal apart from a subtle disorganization of the DMN-derived nerve fibers. In conclusion, regulation of Ret by Nurr1 in midbrain DA neurons and in the DMN has implications for both embryonal development and adult physiology in which signaling by neurotrophic factors plays important roles.

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This receptor and its other subfamily members have emerged as important proteins in different disease states and in the regulation of metabolic tissues, particularly in liver and muscle [6]. The Nurr-1 protein was reported to transcribe growth factors, such as glial cell line-derived neurotrophic factor (GDNF) that activates c-Ret tyrosine kinase receptor [7] and protects organs against cerebral ischemia [8]. Indeed, GDNF stimulates its downstream cascade phosphoinositide 3-kinase (PI3K)/AKT that is commonly considered as a survival pathway [9] to combat the I/R-induced injury via regulating cell proliferation and apoptosis [10].
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On the molecular level, pretreatment with CR and/or MH increased the hepatic contents of Nurr-1, GDNF, and the protein expression of active/p-AKT. On the other hand, they inactivated GSK3β and NF-κB to increase the antioxidant enzymes (GPx, SOD, CAT). All regimens also enhanced the autophagy/lysosomal function and boosted the protein expression of beclin-1, LC3II, and TFEB. Moreover, their antiapoptotic effect was signified by increasing the anti-apoptotic molecule Bcl2 and inhibiting Bax, Bax/Bcl2 ratio, and caspase-3, effects that were confirmed by the TUNEL assay. These improvements were reflected on liver function, as they decreased serum aminotransferases and liver structural alterations induced by I/R. Despite its mild impact, CR₁₀ showed marked improvements when combined with MH; this synergistic interaction overrides the effect of either regimen alone.
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Regular ArticleOrphan Nuclear Receptor Nurr1 Is Essential for Ret Expression in Midbrain Dopamine Neurons and in the Brain Stem

Abstract

Curr. Opin. Neurobiol.

Brain Res.

Cell

J. Auton. Nerv. Syst.

Mol. Cell. Neurosci.

Exp. Neurol.

Neurosci. Lett.

Cell

Exp. Neurol.

J. Biol. Chem.

Cell

Neuron

Mech. Dev.

Brain Res.

Brain Res. Mol. Brain Res.

Exp. Neurol.

Cell

Exp. Cell Res.

Mol. Brain Res.

Atlas of Prenatal Rat Brain Development

Inhibition of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression reduces dopaminergic sprouting in the injured striatum

Eur. J. Neurosci.

Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain

Nature

Complete sequence of a cDNA encoding an active rat choline acetyltransferase: A tool to investigate the plasticity of cholinergic phenotype expression

J. Neurosci. Res.

Sensitive mRNA detection using unfixed tissue: Combined radioactive and non-radioactive in situ hybridization histochemistry

Histochemistry

GDNF signalling through the Ret receptor tyrosine kinase

Nature

Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling

Cell

Respiratory pattern generation in mammals

Neurobiology in the Control of Breathing

Orphan nuclear receptors: From gene to function

Endocr. Rev.

Glial cell line-derived neurotrophic factor is essential for postnatal survival of midbrain dopamine neurons

J. Neurosci.

Regular Article
Orphan Nuclear Receptor Nurr1 Is Essential for Ret Expression in Midbrain Dopamine Neurons and in the Brain Stem