Mest/Peg1 Is 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 that Mest transcript is expressed in the midbrain throughout development and becomes restricted to the substantia nigra (SNc) at late stages. In Mest KO 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 of Lrp6 KO embryos suggest a subtle opposite phenotype to the Mest KO, hinting toward the possibility that specific loss of mdDA neurons in Mest ablated animals could be due to affected WNT-signaling. Interestingly, the mdDA neuronal region affected by the loss of Mest remains relatively unaffected in Pitx3 mutants, 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 of Mest, resemble the loss of SNc neurons and loss of movement control as seen in Parkinson’s Disease (PD), suggesting that the Mest mouse model may be used as a model-system for PD.

Acquisition of the Midbrain Dopaminergic Neuronal Identity

“…These studies show that subset differentiation starts early in development, after which the subgroups segregate even further in molecularly distinct subsets both in the murine and the human brain [ 91 , 106 ]. These studies provide a detailed map of the transcriptome in single cells present in the mdDA neuronal population and validate earlier research on the molecular segregation of mdDA neuronal subsets [ 8 , 96 , 104 ]. However, some subsets of mdDA neurons are not detected in these studies, for instance, the Rspo2 -expressing subgroup in the SN, affected in the Lmx1a mutant [ 52 , 91 , 106 ].…”

“…Considering the amount of Wnts expressed through time in the embryonic midbrain and their disperse effects on mdDA neuronal differentiation, it is likely that regulation of the WNT-signaling cascade could play a major role in late subset specification of mdDA neurons, as was corroborated by recent studies. In a Mest / Peg1 mutant, a protein that modulates WNT-signaling by inhibition of LRP6 maturation, a subset of the SN is lost, indicating that canonical WNT-signaling may be involved in the development of this specific group of cells [ 96 ] ( Figure 2 B). Furthermore, specific deletion of Ezh2 at E12.5 via the Pitx3-Cre driver results in the affected maturation of mdDA neurons in the VTA and SN [ 97 ].…”

Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

“…Although the role of this enzyme in the CNS is not fully understood, it functions as a modulator of the WNT/β-catenin pathway [ 72 ], an essential signal during brain development and in neurological diseases [ 73 ]. Moreover, recent work indicates an essential role of MEST for the development and maintenance of different neuronal subsets in the CNS [ 74 , 75 ]. Interestingly, the hyper-methylation of the MEST CpG island, as we reported after 48 h of TNFα stimulation, could regulate the expression of miR-335, a microRNA involved in fetal development and spatial memory as well as synaptic plasticity [ 76 , 77 ].…”

Imprinted genes influencing the quality of maternal care

“…During fetal development Peg1 is predominantly expressed in mesodermal tissues including heart, lung, cartilage, skeletal muscle and tongue, and also within the remnants of Rathke's pouch, the amygdala, ventral hippocampus, main and accessory olfactory bulbs, cortex, dorsal hippocampus and striatum and the choroid plexus [4; 48]. Expression in the developing mouse midbrain overlaps with mesodiencephalic dopaminergic neurons before becoming restricted to part of the substantia nigra in adults [52].…”