Mesodiencephalic Dopaminergic Neuronal Differentiation Does Not Involve GLI2A-Mediated SHH-Signaling and Is under the Direct Influence of Canonical WNT Signaling

Mesman, Simone; Oerthel, Lars von; Smidt, Marten P.

doi:10.1371/journal.pone.0097926

Cited by 30 publications

(45 citation statements)

References 57 publications

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“…From E9.5 to E11.5 Wnt1 is expressed in the lateral MbDN progenitor domain and with the onset of MbDN neurogenesis Wnt1 is also present in differentiated MbDNs. Wnt1 expression is downregulated in MbDN progenitors at E12.5, but maintained in differentiating MbDNs up to E14.5 [75][76][77][78] (Fig. 3B).…”

Section: Spatial: Molecular Codes Defining Distinct Progenitor Domainsmentioning

confidence: 94%

Establishing diversity in the dopaminergic system

Bodea

Blaess

2015

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a b s t r a c tMidbrain dopaminergic neurons (MbDNs) modulate cognitive processes, regulate voluntary movement, and encode reward prediction errors and aversive stimuli. While the degeneration of MbDNs underlies the motor defects in Parkinson's disease, imbalances in dopamine levels are associated with neuropsychiatric disorders such as depression, schizophrenia and substance abuse. In recent years, progress has been made in understanding how MbDNs, which constitute a relatively small neuronal population in the brain, can contribute to such diverse functions and dysfunctions. In particular, important insights have been gained regarding the distinct molecular, neurochemical and network properties of MbDNs. How this diversity of MbDNs is established during brain development is only starting to be unraveled. In this review, we summarize the current knowledge on the diversity in MbDN progenitors and differentiated MbDNs in the developing rodent brain. We discuss the signaling pathways, transcription factors and transmembrane receptors that contribute to setting up these diverse MbDN subpopulations. A better insight into the processes that establish diversity in MbDNs will ultimately improve the understanding of the architecture and function of the dopaminergic system in the adult brain.

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Section: Spatial: Molecular Codes Defining Distinct Progenitor Domainsmentioning

confidence: 94%

Establishing diversity in the dopaminergic system

Bodea

Blaess

2015

FEBS Letters

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“…MdDA progenitors develop at the ventricular zone of the ventral midbrain (Brodski et al, 2003;Mesman et al, 2014;Ono et al, 2007;Placzek and Briscoe, 2005). Around embryonic day (E) 10.5 the first progenitors exit the cell cycle to give rise to post-mitotic mdDA precursors that will start to express the rate-limiting enzyme of DA synthesis, Tyrosine Hydroxylase (TH) (Bayer et al, 1995).…”

Section: En1cre/+; Ezh2 L/l Embryos Display a Disorganized Mdda Domaimentioning

confidence: 99%

EZH2 influences mdDA neuronal differentiation, maintenance and survival

Wever

Oerthel

Wagemans

et al. 2018

Preprint

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Over the last decade several components have been identified to be differentially expressed in subsets of mesodiencephalic dopaminergic (mdDA) neurons. These differences in molecular profile have been implied to be involved in the selective degeneration of the SNc neurons in Parkinson's disease. The emergence and maintenance of individual subsets is dependent on different transcriptional programs already present during development. In addition to the influence of transcription factors, recent studies have led to the hypothesis that modifications of histones might also influence the developmental program of neurons. In this study we focus on the histone methyltransferase EZH2 and its role in the development and maintenance of mdDA neurons. We generated two different conditional knock out (cKO) mice; an En1Cre driven cKO, for deletion of Ezh2 in mdDA progenitors and a Pitx3Cre driven cKO, to study the effect of post-mitotic deletion of Ezh2 on mdDA neurons maturation and neuronal survival. During development Ezh2 was found to be important for the generation of the proper amount of TH+ neurons. The loss of neurons primarily affected a rostrolateral population, which is also reflected in the analysis of the subset marks, Ahd2 and Cck. In contrast to early genetic ablation, post-mitotic deletion of Ezh2 did not lead to major developmental defects at E14.5. However, in 6 months old animals Cck was found ectopically in the rostral domain of mdDA neurons and Ahd2 expression was reduced in more mediocaudal positioned cells. In addition, Pitx3Cre driven deletion of Ezh2 led to a progressive loss of TH+ cells in the VTA and these animals display reduced climbing behavior. Together, our data demonstrates that Ezh2 is important for the generation of mdDA neurons during development and that during adult stages Ezh2 is important for the preservation of proper neuronal subset identity and survival.

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“…This type of signaling is also known to be relevant during brain development, suggesting that Mest may serve a similar function during development of the central nervous system. Both canonical and non-canonical WNT-signaling have been reported to be important in the development and specification of mdDA neurons (Castelo-Branco et al, 2004; Schulte et al, 2005; Cajánek et al, 2009; Mesman et al, 2014). If MEST similarly regulates the maturation of LRP6 during mdDA neuronal development, it could play an important role in the onset of mdDA neuronal specification and differentiation.…”

Section: Introductionmentioning

confidence: 99%

Mest/Peg1 Is Essential for the Development and Maintenance of a SNc Neuronal Subset

Mesman

Hooft

Smidt

2017

Front. Mol. Neurosci.

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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.

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Mesodiencephalic Dopaminergic Neuronal Differentiation Does Not Involve GLI2A-Mediated SHH-Signaling and Is under the Direct Influence of Canonical WNT Signaling

Cited by 30 publications

References 57 publications

Establishing diversity in the dopaminergic system

Establishing diversity in the dopaminergic system

EZH2 influences mdDA neuronal differentiation, maintenance and survival

Mest/Peg1 Is Essential for the Development and Maintenance of a SNc Neuronal Subset

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