Research article

Elevated P75^NTR expression causes death of engrailed-deficient midbrain dopaminergic neurons by Erk1/2 suppression

Kambiz N Alavian^1,2 , Paola Sgadò^1,3 , Lavinia Alberi^1,4 , Srinivasa Subramaniam^1,5 and Horst H Simon¹

¹  Interdisciplinary Centre for Neuroscience, Department of Neuroanatomy, Ruprecht-Karls-Universität, 69120 Heidelberg, Germany

²  Harvard Medical School, Neuroregeneration Labs, MRC 1, McLean Hospital, Mill St, Belmont, MA 02478, USA

³  Paola Sgadò, Neurogenetics Laboratory, Child Neurology Unit, Pediatric Hospital A Meyer, Piazza di Careggi, 50139 Florence, Italy

⁴  The Johns Hopkins Institute for Cell Engineering, Department of Neurology, North Broadway Street, BRB 720, Baltimore, MD 2120, USA

⁵  Department of Neuroscience, Johns Hopkins Medical School, N Wolfe Street, Baltimore, MD 21210, USA

author email corresponding author email

Neural Development 2009, 4:11doi:10.1186/1749-8104-4-11

Published:	16 March 2009

Abstract

Background

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-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.

Results

In this work, we show that the dose of Engrailed is inversely correlated to the expression level of the pan-neurotrophin receptor gene P75^NTR (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 P75^NTR 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 P75^NTR, 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.

Conclusion

Our study links the survival function of the Engrailed genes in developing mesDA neurons to the regulation of P75^NTR 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 P75^NTR that alter their expression levels could, in part, determine susceptibility to Parkinson's disease.