Elevated P75NTR expression causes death of engrailed-deficient midbrain dopaminergic neurons by Erk1/2 suppression

Kambiz N Alavian,Horst H Simon,Paola Sgadò,Srinivasa Subramaniam,Lavinia Alberi

doi:10.1186/1749-8104-4-11

Kambiz N Alavian, Horst H Simon + Show 3 more

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https://doi.org/10.1186/1749-8104-4-11

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Abstract

BackgroundThe homeodomain transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic (mesDA) neurons in a cell-autonomous and gene-dose-dependent manner. Homozygote mutant mice, deficient of both genes (En1-/-;En2-/-), die at birth and exhibit a loss of all mesDA neurons by mid-gestation. In heterozygote animals (En1+/-;En2-/-), which are viable and fertile, postnatal maintenance of the nigrostriatal dopaminergic system is afflicted, leading to a progressive degeneration specific to this subpopulation and Parkinson's disease-like molecular and behavioral deficits.ResultsIn this work, we show that the dose of Engrailed is inversely correlated to the expression level of the pan-neurotrophin receptor gene P75NTR (Ngfr). Loss of mesDA neurons in the Engrailed-null mutant embryos is caused by elevated expression of this neurotrophin receptor: Unusually, in this case, the cell death signal of P75NTR is mediated by suppression of Erk1/2 (extracellular-signal-regulated kinase 1/2) activity. The reduction in expression of Engrailed, possibly related to the higher levels of P75NTR, also decreases mitochondrial stability. In particular, the dose of Engrailed determines the sensitivity to cell death induced by the classic Parkinson-model toxin MPTP and to inhibition of the anti-apoptotic members of the Bcl-2 family of proteins.ConclusionOur study links the survival function of the Engrailed genes in developing mesDA neurons to the regulation of P75NTR and the sensitivity of these neurons to mitochondrial insult. The similarities to the disease etiology in combination with the nigral phenotype of En1+/-;En2-/- mice suggests that haplotype variations in the Engrailed genes and/or P75NTR that alter their expression levels could, in part, determine susceptibility to Parkinson's disease.

Highlights

The homeodomain transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dosedependent manner
EFliegvuarteed1P75NTR expression is causal for cell death Elevated P75NTR expression is causal for cell death. (A) Quantitative RT-PCR of ventral midbrain tissue (VM) derived from Engrailed double mutant mice (EnDM) (En1-/-;En2-/-) and En1 heterozygote (EnHT) E12 embryos, and of En1-expressing N2A cells inducible by doxycycline (Dox)
Silencing of P75NTR by double-stranded RNA oligos and application of P75NTR-inhibiting antibody (Rex) increases the survival rate of EnDM mesencephalic dopaminergic (mesDA) neurons compared to untreated control (Ctl) or after treatment with scrambled RNA oligos (n ≥ 6, p < 0.01)

Summary

Introduction

The homeodomain transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic (mesDA) neurons in a cell-autonomous and gene-dosedependent manner. Mesencephalic dopaminergic (mesDA) neurons are the main source of dopamine in the mammalian central nervous system. They are located in three distinct nuclei, substantia nigra pars compacta, ventral tegmentum and retrorubral field. Their main innervation targets are the basal ganglia, where they play key roles in the control of emotion, motivation and motor behavior, documented by their connection to schizophrenia, addiction and, most prominently, to Parkinson's disease (PD) [1,2]. The main characteristic of PD is the slow progressive loss of dopaminergic neurons in the substantia nigra pars compacta, causing diminished release of dopamine in the caudate putamen and debilitating motor deficits. Mitochondrial insult can cause oxidative stress by production of reactive oxygen species, leading to increased permeability of the mitochondrial membrane, release of pro-apoptotic molecules, including cytochrome-C, into the cytoplasm and, subsequently, to activation of caspases and induction of apoptosis [7]

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