title: Mest/Peg1Is Essential for the Development and Maintenance of a SNc Neuronal Subset.
abstract: Mesodiencephalic dopaminergic (mdDA) neurons originate at the floor plate and floor plate-basal plate boundary of the midbrain ventricular zone. During development mdDA neurons are specified by a unique set of transcription factors and signaling cascades, to form the different molecular subsets of the mdDA neuronal population. In a time series micro-array study performed previously, mesoderm specific transcript (Mest) was found to be one of the most upregulated genes during early mdDA neuronal development. Here, we show thatMesttranscript is expressed in the midbrain throughout development and becomes restricted to the substantia nigra (SNc) at late stages. InMestKO animals mdDA neurons are progressively lost in the adult, mostly affecting the SNc, reflected by a 50% decrease of TH protein and DA release in the striatum and a reduction of climbing behavior. Analysis ofLrp6KO embryos suggest a subtle opposite phenotype to theMestKO, hinting toward the possibility that specific loss of mdDA neurons inMestablated animals could be due to affected WNT-signaling. Interestingly, the mdDA neuronal region affected by the loss ofMestremains relatively unaffected inPitx3mutants, suggesting that both genes are essential for the development and/or maintenance of different mdDA neuronal subsets within the SNc. Overall, the neuroanatomical and phenotypical consequences detected upon the loss ofMest, resemble the loss of SNc neurons and loss of movement control as seen in Parkinson's Disease (PD), suggesting that theMestmouse model may be used as a model-system for PD.
authors.affiliation: Swammerdam Institute for Life Sciences, FNWI University of Amsterdam Amsterdam, Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Mesman
authors.affiliation: Swammerdam Institute for Life Sciences, FNWI University of Amsterdam Amsterdam, Netherlands.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: van Hooft
authors.affiliation: Swammerdam Institute for Life Sciences, FNWI University of Amsterdam Amsterdam, Netherlands.
authors.forename: Marten P
authors.initials: MP
authors.lastname: Smidt
keywords: Parkinson’s disease; degeneration; dopamine; midbrain; neuronal development