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EH004: Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/b-catenin signaling activator Rspo2

ABSTRACT: Recent developments in molecular programming of mesodiencephalic dopaminergic (mdDA) neurons have led to the identification of many transcription factors playing a role in mdDA specification. LIM homeodomain transcription factor Lmx1a is essential for chick mdDA development, and for the efficient differentiation of ES-cells towards a dopaminergic phenotype. In this study, we aimed towards a more detailed understanding of the subtle phenotype in Lmx1a-dr/dr mice. Therefore, microarray analysis was performed, to elucidate the exact molecular programming underlying the neuronal deficits after loss of Lmx1a. Subsequent expression analysis confirmed that Nurr1 is regulated by Lmx1a, and additional downstream targets were identified, like Pou4f1, Pbx1, Pitx2, C130021l20Rik, Calb2 and Rspo2. In line with a specific, rostral-lateral loss of expression of most of these genes during development, Nurr1 and C130021l20Rik were affected in the SNc of the mature mdDA system. Interestingly, this deficit was marked by the complete loss of the Wnt/b-catenin signaling activator Rspo2 in this domain. Expression analysis in Rspo2-/- embryos revealed affected mdDA neurons, partially phenocopying the Lmx1a mutant. Together, in this study we reveal that Lmx1a is essential for a rostral-lateral subset of the mdDA neuronal field, where it might serve a critical function in modulating proliferation and differentiation of mdDA progenitors through the activation of the Wnt activator Rspo2.

ORGANISM(S): Mus musculus

PROVIDER: GSE45831 | GEO | 2013/12/13

SECONDARY ACCESSION(S): PRJNA196515

REPOSITORIES: GEO

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EH004: Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/b-catenin signaling activator Rspo2

Project description:Recent developments in molecular programming of mesodiencephalic dopaminergic (mdDA) neurons have led to the identification of many transcription factors playing a role in mdDA specification. LIM homeodomain transcription factor Lmx1a is essential for chick mdDA development, and for the efficient differentiation of ES-cells towards a dopaminergic phenotype. In this study, we aimed towards a more detailed understanding of the subtle phenotype in Lmx1a-dr/dr mice. Therefore, microarray analysis was performed, to elucidate the exact molecular programming underlying the neuronal deficits after loss of Lmx1a. Subsequent expression analysis confirmed that Nurr1 is regulated by Lmx1a, and additional downstream targets were identified, like Pou4f1, Pbx1, Pitx2, C130021l20Rik, Calb2 and Rspo2. In line with a specific, rostral-lateral loss of expression of most of these genes during development, Nurr1 and C130021l20Rik were affected in the SNc of the mature mdDA system. Interestingly, this deficit was marked by the complete loss of the Wnt/b-catenin signaling activator Rspo2 in this domain. Expression analysis in Rspo2-/- embryos revealed affected mdDA neurons, partially phenocopying the Lmx1a mutant. Together, in this study we reveal that Lmx1a is essential for a rostral-lateral subset of the mdDA neuronal field, where it might serve a critical function in modulating proliferation and differentiation of mdDA progenitors through the activation of the Wnt activator Rspo2. Microarray expression study comparing 4 samples of homozygous LMX1A dr/dr mice, midbrain E12.5 with a pooled sample of their wt/wt littermates. Two samples were analyzed in opposite dye orientation.

2013-12-13 | E-GEOD-45831 | biostudies-arrayexpress

EH001: Lmx1a is an activator of Rgs4 and Gbr10 and is responsible for the correct specification of rostral and medial mdDA neurons

Project description:The LIM homeodomain transcription factor Lmx1a is a very potential inducer of stem cells towards dopaminergic neurons. Despite several studies on the function of this gene, the exact in vivo role of Lmx1a in mesodiencephalic dopamine (mdDA) neuronal specification is still not understood. To analyze the genes functioning downstream of Lmx1a, we performed expression microarray analysis of LMX1A overexpressing MN9D dopaminergic cells. Several interesting regulated genes were identified, based on their regulation in other, previously generated expression arrays, and their expression pattern in the developing mdDA neuronal field. Post analysis through in vivo expression analysis in Lmx1a mouse mutant (drJ/drJ) embryos demonstrated a clear decrease in expression of the genes Grb10 and Rgs4, in and adjacent to the rostral and dorsal mdDA neuronal field and within the Lmx1a expression domain. Interestingly, the DA marker Vmat2 was significantly up-regulated as a consequence of increased LMX1A dose, and subsequent analysis on Lmx1a mutant E14.5 and adult tissue revealed a significant decrease in Vmat2 expression in mdDA neurons. Taken together, microarray analysis of an LMX1A overexpression cell system resulted in the identification of novel downstream targets of Lmx1A in mdDA neurons: Grb10, Rgs4 and Vmat2.

2013-01-08 | GSE39174 | GEO

EH001: Lmx1a is an activator of Rgs4 and Gbr10 and is responsible for the correct specification of rostral and medial mdDA neurons

2013-01-08 | E-GEOD-39174 | biostudies-arrayexpress

Dopaminergic subset specification as a model for molecular mechanisms of neural vulnerability in Parkinson's Disease

Project description:Mesodiencephalic dopaminergic (mdDA) neurons critically regulate locomotory behavior and emotion, and dysfunction is associated with psychiatric and neurodegenerative diseases, including Parkinson's Disease (PD). A pathological hallmark of PD is the specific degeneration of Substantia Nigra (SN) neurons, whereas Ventral Tegmental Area (VTA) neurons are relatively unaffected. Differential molecular programming of the developing SN versus VTA may underly this specific vulnerability, and indeed molecularly distinct mdDA subsets have been identified during development. Driven by the hypothesis that the molecular signature of the SN and VTA originates from differential developmental programming and position along the rostral/caudal axis, we performed genome-wide expression profiling of FACS-purified rostral versus caudal mdDA neurons. Here, we present the distinct transcriptomes of these mdDA subsets and demonstrate how, on a genome-wide scale: 1) transcription factor regulation relates to developmental position, 2) rostral and caudal mdDA neurons differ in their functional genome, 3) the molecular signature of rostral versus caudal mdDA neurons relates to the SN versus VTA molecular profile in adult mice and human and 4) human homologues of rostrally enriched genes are mostly downregulated in the SN of PD patients. Our analyses substantiate the relationship of developmental positions with the SN versus VTA distinction in adult, and suggest cross-species conservation of molecular programs. Driven by these observations, we present 69 target genes that are rostral enriched and downregulated in PD, and thus provide new leads for the investigation of both the complex coding of developing mdDA subsets and and the molecular mechanisms underlying subset-specific vulnerability in PD.

2016-12-31 | GSE57424 | GEO

FJ004: Dopaminergic subset specification as a model for molecular mechanisms of neuronal vulnerability in Parkinson's Disease

2024-08-29 | GSE57234 | GEO

Mus musculus

Project description:EH004: Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/b-catenin signaling activator Rspo2

| PRJNA196515 | ENA

KC001: Genome wide expression profiling of the mesodiencephalic region led to the identification of novel factors involved in early and late dopaminergic development.

Project description:Meso-diencephalic dopaminergic (mdDA) neurons are critical for motor control and cognitive functioning and their loss or dysfunction is associated with disorders such as Parkinson’s disease (PD), schizophrenia and addiction. However, relatively little is known about the molecular mechanisms underlying mdDA neuron development and maintenance. Here, we determined the spatiotemporal map of genes involved in the development of mdDA neurons to gain further insights into their molecular programming. Genome-wide gene expression profiles of the developing ventral mesencephalon (VM) were compared at different developmental stages leading to the identification of novel regulatory roles of neuronal signaling through nicotinic acthylcholine receptors (Chrna6 and Chrnb3 subunits) and the identification of novel transcription factors (OC1 and 2)) involved in the generation of mdDA neuronal field. We show here that Pitx3 in cooperation with Nurr1 are the critical components in the activation of the Chrna6 and b3 subunits in mdDA neurons. Furthermore, we provide evidence of two divergent regulatory pathways resulting in the expression of Chrna6 and Chrnb3 respectively.

2012-07-09 | GSE35326 | GEO

Dose-dependent and subset-specific regulation of midbrain dopaminergic neuron differentiation by LEF1-mediated WNT1/b-Catenin signaling

Project description:The development of the mesodiencephalic dopaminergic (mdDA) neurons strongly depends on the WNT1/b-catenin signaling pathway. These neurons include the Substantia nigra pars compacta (SNc) subset that preferentially degenerates in Parkinson’s Disease (PD), and the ventral tegmental area (VTA) subpopulation implicated in a variety of neuropsychiatric disorders. The identity of the cells responding to this signaling pathway in the developing mammalian ventral midbrain (VM) and the precise mechanism of WNT/b-catenin action in these cells, however, are still unknown. Moreover, this signaling pathway has to be accurately balanced during mdDA neuron development: whereas low levels or absence of WNT1/b-catenin signaling abolish their correct specification, constitutive activation of this signaling pathway prevents their proper differentiation in the mouse. We show that the WNT/b-catenin-responsive cells constitute only a fraction of all mdDA progenitors, precursors and neurons in the murine VM. These WNT/b-catenin-responsive cells are mostly located in the Wnt1+, Rspo2+ and Lef1+ lateral floor plate of the medial and caudal midbrain, giving preferentially rise to caudomedial (VTA) mdDA neurons. Strong WNT/b-catenin signaling mediated by RSPO2, a WNT/b-catenin agonist, and LEF1, a nuclear effector of this pathway, inhibits the differentiation of WNT/b-catenin-responsive mdDA progenitors into mature mdDA neurons by repressing the murine Pitx3 gene via conserved LEF1/TCF binding sites in its promoter. Our data indicate that an attenuation of WNT/b-catenin signaling in mdDA progenitors is essential for their correct differentiation into specific mdDA neuron subsets, thus providing a new means for stem cell-based regenerative therapies of PD and in vitro models of neuropsychiatric diseases.

2020-09-02 | GSE99618 | GEO

Enrichment, proteome analysis and transplantation of human embryonic stem cell derived dopaminergic progenitors expressing LMX1a

Project description:Despite the progress in safety and efficacy of cell therapy with pluripotent stem cells (PSCs), the presence of residual undifferentiated stem cells or proliferating neural progenitor cells (NPCs) with rostral identity has remained a major challenge. Here we reported the generation of an LMX1A knock-in GFP reporter human embryonic stem cell (hESC) line that marks the early dopaminergic progenitors during neural differentiation. Purified GFP positive cells in vitro exhibited expression of mRNA and proteins that characterized and matched the midbrain dopaminergic identity. Further proteomic analysis of enriched LMX1A+ cells identified several membrane associated proteins including CNTN2, enabling prospective isolation of LMX1A+ progenitor cells. Transplantation of hPSC-derived purified CNTN2+ progenitors enhanced dopamine release from transplanted cells in the host brain and alleviated Parkinson’s disease symptoms in animal models. Our study establishes an efficient approach for purification of large numbers of hPSC-derived dopaminergic progenitors for therapeutic applications.

2018-06-06 | PXD007837 | Pride

KC001: Genome wide expression profiling of the mesodiencephalic region led to the identification of novel factors involved in early and late dopaminergic development.

2012-07-08 | E-GEOD-35326 | biostudies-arrayexpress