Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons

Abstract

Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional Nurr1 genetargeted mice in which Nurr1 is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that Nurr1 ablation results in a progressive pathology associated with reduced striatal DA, impaired motor behaviors, and dystrophic axons and dendrites. We used laser-microdissected DA neurons for RNA extraction and next-generation mRNA sequencing to identify Nurr1-regulated genes. This analysis revealed that Nurr1 functions mainly in transcriptional activation to regulate a battery of genes expressed in DA neurons. Importantly, nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1-regulated target genes. These studies indicate that Nurr1 has a key function in sustaining high respiratory function in these cells, and that Nurr1 ablation in mice recapitulates early features of Parkinson's disease. NR4A2 | nuclear receptor | laser capture microdissection | RNA sequencing | orphan receptor U nder experimental conditions, somatic differentiated cells can undergo reprogramming into other cell types or induced pluripotent stem cells (1). This remarkable plasticity raises questions of how the differentiated cellular identity is maintained for extended periods in normal life (2). Of particular relevance is how neurons, which should retain their specific functions for decades in a human brain, stably maintain their unique differentiated properties, and how disrupted maintenance of the correct differentiated identity may be related to disease. Under embryonic development, signaling events induce the expression of transcription factors that combinatorially function to specify appropriate identities and differentiation of specific neuron types. Many of these transcription factors continue to be expressed in adult neurons as well; however, little is known of their functions in the adult brain, or the extent to which they contribute to the stability of the differentiated state (3).Degeneration of ventral midbrain (VMB) dopamine (DA) neurons, particularly neurons of the substantia nigra compacta (SNc), causes many of the characteristic symptoms in patients with Parkinson's disease (PD). PD is characterized by a progressive pathology involving the appearance of insoluble protein inclusions known as Lewy bodies and eventually the death of neurons. Several studies have indicated that loss of striatal DA and other dopaminergic properties cause symptoms in PD long before cell bodies within the SNc actually die (4). Thus, PD cell pathology may influence differentiated...

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

“…Because other genetic mouse models with a moderate reduction in DA content similar to that of adult Foxa1/2 cKO mice do not lead to an aphagic phenotype (22,77), we therefore speculate that our model represents a scenario whereby a 50% reduction in DA content in combination with a reduction of burst firing together impair both the quantity and the temporal control of DA release in the striatum. This dysregulation primarily contributes to aphagia due to lack of motivation to feed/drink (37), whereas overall activity/motor function remains unaffected.…”

“…4A). In addition, we quantified the expression levels of Pitx3 and Nr4a2, two transcription factors also expressed in adult mDA neurons (22,35). We found that neither Pitx3 nor Nr4a2 expression A B C Fig.…”

“…For example, OTX2 expression is restricted to the VTA in adult mDA neurons and is necessary to control VTA identity and to protect these neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated toxic insults (21). In addition, NURR1 has recently been found to sustain nuclear-encoded mitochondrial gene expression and to preserve neurite integrity of adult mDA neurons (22). A recent study from our laboratory demonstrated that late developmental inactivation of FOXA1/2 in mDA neurons leads to a phenotypic change, and mDA neurons lose their DAergic markers without incurring cell loss (23).…”

Is Axonal Degeneration a Key Early Event in Parkinson’s Disease?

“…This research was elegantly summarized by Dr. Robert Burke in his talk and recent review [9]. The models that were discussed include: AAV/2 human a-syn-A53T in rat [10], AAV/6 human a-syn-WT in rat [11], hBAC-LRRK2 in mouse [12,13], mBAC-Nurr1(fl/fl)XmBACDAT-CreT2 in mouse [14] and Engrailed1 +/-mouse [15,16], and it is likely that there are other models where such changes are yet to be reported. All of them present some form of axonal abnormalities in TH-positive nigrostriatal fibers before the degenerative processes are detected in the cell bodies.…”

“…Similar axonal spheroids were described in the post-mortem brains of PD [18] and Diffuse Lewy Body Disease patients [19], and they are also seen in other neurodegenerative diseases such as multiple sclerosis (MS). In aforementioned rodent models, the axo-degenerative processes are accompanied by other axonal abnormalities that mimic findings made in PD, such as loss of dopaminergic phenotype [11,14,15], changes in levels of axonal transport proteins [10], and autophagy markers [15]. 'It is important to emphasize that although this evidence suggests that axons are the first site of degenerative change, this does not necessarily mean that the primary disturbance at the molecular level first occurs in the axons.…”