Nurr1 Expression and Its Modulation in Microglia

Abstract

Objective:Nurr1, a transcription factor essential for the differentiation and maturation of central dopaminergic cells, is primarily expressed in neurons of the central nervous system. In this study, we intend to determine the expression and modulation of Nurr1 in cultured microglia. Methods: Nurr1 expression in cultured primary mouse microglia was measured by reverse transcription polymerase chain reaction, Western blot and immunofluorescent staining. Lipopolysaccharide (LPS) was used to activate microglia. Specific inhibitors were used to investigate whether the mitogen- activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), MAPK/Jun N-terminal kinase (JNK), P38 MAPK and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways were involved in the modulation of Nurr1 expression.Results: Nurr1 was found to be located at both the cytoplasm and the nucleus of the microglia. After LPS stimulation, the expression of Nurr1 was significantly increased, which could be partially blocked by inhibitors of ERK, JNK and PI3K/Akt, but not by the P38 MAPK inhibitor; the ERK inhibitor can partially block the translocation of Nurr1 from the cytoplasm to the nucleus. Conclusion: Nurr1 is found to be expressed in cultured mouse microglia. The expression of Nurr1 is increased and the protein is translocated from the cytoplasm to the nucleus after activation by LPS, which could be modulated by the ERK, JNK and PI3K/Akt pathways.

Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1

“…Although several potential mechanisms for this neuroprotection are possible, the ability of valproate to increase Nurr1 expression and binding to promoter regions of catecholamine genes, including the DAT, tyrosine hydroxylase and the vesicular monoamine transporter 2 (Smits et al, 2003) may result in maintenance of these phenotypic markers of dopamine neurons during neurodegeneration. Moreover, Nurr1 has recently been demonstrated to play an important role in dampening neuroinflammation through its action in microglia (Fan et al, 2009; Saijo et al, 2009), which would be expected to be protective in Parkinson’s disease. Additional studies will be required to determine the relative roles of these potential mechanisms in the neuroprotective effects of valproate.…”

Inflammatory response in Parkinson’s disease (Review)

“…Following LPS stimulation, the expression levels of Nurr1 were markedly increased, which could be blocked by inhibitors of ERK, JNK and PI3K/Akt. The ERK inhibitor was shown to partially block the translocation of Nurr1 from the cytoplasm to the nucleus (163). Bensinger and Tontonoz (164) also indicated that Nurr1 protects DA neurons by suppressing inflammatory gene expression in astrocytes and microglia.…”

Ropinirole alters gene expression profiles in SH-SY5Y cells: a whole genome microarray study

“…This indicated that ROP might exert neuroprotective effects through the PI3K pathway, and that PIK3C2B might play a role in this process. Additionally, we previously observed that the PI3K/Akt pathway modulates the expression of Nurr1, which is a transcription factor essential for the differentiation and maturation of central dopaminergic cells ( 15 ). This suggested that ROP might induce PIK3C2B and modulate Nurr1 to exert neuroprotection.…”