Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice.
The homeobox transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dose-dependent manner. Because of this requirement, the cells die by apoptosis when all four alleles of the Engrailed genes are genetically ablated (En1-/-;En2-/-). In the present study, we show that viable and fertile mice, heterozygous null for Engrailed-1 and homozygous null for Engrailed-2 (En1+/-;En2-/-), have an adult phenotype that resembles key pathological features of Parkinson's disease. Specifically, postnatal mutant mice exhibit a progressive degeneration of dopaminergic neurons in the substantia nigra during the first 3 mo of their lives, leading to diminished storage and release of dopamine in the caudate putamen, motor deficits similar to akinesia and bradykinesia, and a lower body weight. This genetic model may provide access to the molecular etiology for Parkinson's disease and could assist in the development of novel treatments for this neurodegenerative disorder.
Sgadò
Paola
P
Interdisciplinary Center for Neuroscience, Department of Neuroanatomy, Ruprecht-Karls Universität Heidelberg, 69120 Heidelberg, Germany.
Albéri
Lavinia
L
Gherbassi
Daniel
D
Galasso
Sherri L
SL
Ramakers
Geert M J
GM
Alavian
Kambiz N
KN
Smidt
Marten P
MP
Dyck
Richard H
RH
Simon
Horst H
HH
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D013378:Substantia Nigra / Q000473:pathology* / Q000502:physiology; D000099266:Engrailed 2 Protein
D004298:Dopamine; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000099266:Engrailed 2 Protein; C080330:En1 protein, mouse