Transcription factor Sp9 is a negative regulator of D1-type MSN development [scRNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE202523 | GEO | 2022/07/06
REPOSITORIES: GEO
Similar Datasets
Project description:The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate. The striatum is the main input structure of the basal ganglia, receiving information from the cortex and the thalamus and consisting of D1- and D2- medium spiny neurons (MSNs). D1-MSNs and D2-MSNs are essential for motor control and cognitive behaviors and have implications in Parkinson’s Disease. In the present study, we demonstrated that Sp9 positive progenitors produced both D1-MSNs and D2-MSNs and that Sp9 expression was rapidly downregulated in postmitotic D1-MSNs. Furthermore, we found that sustained Sp9 expression in lateral ganglionic eminence (LGE) progenitor cells and their descendants led to promoting D2-MSNs identity and repressing D1-MSNs identity during striatal development. As a result, sustained Sp9 expression resulted in an imbalance between D1-MSNs and D2-MSNs in the mouse striatum. In addition, the fate-changed D2 like-MSNs survived normally in adulthood. Taken together, our finding supported that Sp9 was sufficient to promote D2-MSNs identity and repress D1-MSNs identity, and Sp9 was a negative regulator of D1-MSNs fate.
2022-07-06 | GSE202550 | GEO
Project description:D1- and D2-type medium spiny neurons (MSNs) are the principal projection neurons in the striatum, including in the dorsal striatum (caudate nucleus and putamen) and ventral striatum (nucleus accumbens and olfactory tubercle) that are generated by the lateral ganglionic eminence (LGE). Using conditional deletion, we show that mice lacking the Sp8 and Sp9 transcription factors (TFs) selectively have a severe reduction in D2 MSNs due to reduced neurogenesis in the LGE. Sp8/9 together drive expression of the Six3 TF in a spatial restricted domain of the LGE subventricular zone. Conditional deletion of Six3 also prevents the formation of most D2 MSNs, phenocopying the Sp8/9 loss of function. Finally, ChIP-Seq reveals that SP9 directly binds to the promoter and a putative enhancer of Six3. This study provides evidence for components of a transcription pathway, in a regionally restricted LGE domain, that selectively drives the generation of D2 MSNs.
2018-05-11 | GSE114306 | GEO
Project description:The striatum is primarily composed of two types of medium spiny neurons (MSNs) expressing either D1- or D2-type dopamine receptors. However, the fate determination of these two types of neurons is not fully understood. Here, we found that D1 MSNs undergo fate switching to D2 MSNs in the absence of Zfp503. Furthermore, scRNA-seq revealed that the transcription factor Zfp503 affects the differentiation of these progenitor cells in the lateral ganglionic eminence (LGE). More importantly, we found that the transcription factors Sp8/9, which are required for the differentiation of D2 MSNs, are repressed by Zfp503.
2022-09-20 | GSE202439 | GEO
Project description:Purpose: To assess changes in gene expression profiles from the P0 littermate Sp9Flox/Flox control striatum (including SVZ) and conditional mutant striatum of Drd2-Cre; Sp9Flox/Flox mice. Methods: total RNA was isolated and sequenced from the striatum of the P0 littermate Sp9Flox/Flox control or conditional mutant striatum of Drd2-Cre; Sp9Flox/Flox mice in triplicate using an Illumina high-seq 2500. Raw data was analyzed using TopHat. Genes were considered changed which demonstrated fold-change>=2, and p value <=0.05. Changed genes were then filtered to reveal Sp9 downstream targets which were altered in vivo due to the loss of Sp9 expression. Results: 179 genes were significantly increased and 147 genes were significantly decreased in expression level due to the loss of Sp9 expression. total RNA was isolated and sequenced from the striatum of the P0 littermate Sp9Flox/Flox control or conditional mutant striatum of Drd2-Cre; Sp9Flox/Flox mice in triplicate using an Illumina high-seq 2500. Raw data was analyzed using TopHat. Genes were considered changed which demonstrated fold-change>=2, and p value <=0.05. Changed genes were then filtered to reveal Sp9 downstream targets which were altered in vivo due to the loss of Sp9 expression.
2016-06-16 | E-GEOD-83373 | biostudies-arrayexpress
Project description:Use of addictive substances often creates powerful and enduring associations with external cues that act as relapse triggers in individuals recovering from a substance use disorder (SUD). In the reward-associated brain region, the nucleus accumbens (NAc), drug use or drug-associated cue exposure activates a subset of D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs), which typically promotes drug seeking, and a smaller subset of D2 dopamine receptor-expressing MSNs (D2-MSNs), which typically opposes drug seeking. The activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), is activated in a small subset of NAc neurons during cocaine conditioning, and NAc NPAS4 is required for drug-context memories. Using a new Npas4-TRAP mouse combined with chemogenetics, we found that the during cocaine conditioning, the NPAS4-positive ensemble is required for drug-context associations. Single-cell transcriptomic analyses and in situ hybridization of NAc tissues from drug-conditioned mice revealed that NPAS4 is expressed predominantly in MSNs, and using cell type-specific molecular genetic approaches, we found that NPAS4 in D2-MSNs, but not D1-MSNs, was required for both drug-context associations and cue-reinstated cocaine seeking. Similarly, NPAS4 in NAc D2-MSNs, but not D1-MSNs, blocked cocaine experience-dependent strengthening of glutamatergic prefrontal cortical (PFC) inputs onto D2-MSNs. Analysis of differential gene expression in D2-MSNs revealed that NPAS4 and cocaine conditioning influence a gene expression program associated with synapses, dendrites, neuronal projections, dopamine, and cocaine. Together, our data reveal that NPAS4 functions during active cocaine use to maintain the imbalance of D1-MSN:D2-MSN activation and cue-induced drug seeking by suppressing excitatory drive onto relapse-opposing NAc D2-MSN circuits.
2023-08-31 | GSE210850 | GEO
Project description:Purpose: To assess changes in gene expression profiles from the P0 littermate Sp9Flox/Flox control striatum (including SVZ) and conditional mutant striatum of Drd2-Cre; Sp9Flox/Flox mice. Methods: total RNA was isolated and sequenced from the striatum of the P0 littermate Sp9Flox/Flox control or conditional mutant striatum of Drd2-Cre; Sp9Flox/Flox mice in triplicate using an Illumina high-seq 2500. Raw data was analyzed using TopHat. Genes were considered changed which demonstrated fold-change>=2, and p value <=0.05. Changed genes were then filtered to reveal Sp9 downstream targets which were altered in vivo due to the loss of Sp9 expression. Results: 179 genes were significantly increased and 147 genes were significantly decreased in expression level due to the loss of Sp9 expression.
2016-06-16 | GSE83373 | GEO
Project description:Variations in the human FTO gene have been linked to obesity and altered connectivity and function of the dopaminergic neurocircuitry. Here we report that FTO in D2 medium spiny neurons (MSNs) of mice regulates the excitability of these cells in vitro and in vivo as well as controls D2 MSN globus pallidus external projections. Lack of FTO in D2 MSNs translates into increased locomotor responses to novelty, associated with altered timing behavior without affecting reward responses to drugs of abuse and highly palatable food, or the ability to discount rewards. Pharmacological manipulation of D1R- and D2R-dependent pathways in these animals reveals an altered balance between D1 MSN- and D2 MSN-mediated control of motor output. These findings hold the potential to target a novel avenue for control of basal ganglia motor function, where modulation of FTO-dependent signaling in D2 MSNs may promote D1 MSN regulated locomotor behavior without altering reward signaling or inciting impulsivity.
2019-06-14 | PXD013738 | Pride
Project description:Purpose: To assess changes in gene expression profiles from the E16.5 no cre littermate control striatum and conditional double knockout of Dlx5/6-CIE; Sp8 Flox/Flox; Sp9 Flox/Flox mice. Methods: Total RNA was isolated and sequenced from the striatum of the E16.5 no cre littermate control or Dlx5/6-CIE; Sp8 Flox/Flox; Sp9 Flox/Flox mice in duplicate using an illumina high-seq 2500. Raw data was analyzed using TopHat. Genes were considered changed which performed fold-change>=2 and FDR<=0.05. Changed genes were then filtered to reveal the downstream targets of Sp8 and Sp9. Results: 80 genes were significantly increased and 120 genes were significantly decreased in expression level due to the loss of Sp8 and Sp9 expression.
2018-05-11 | GSE102865 | GEO
Project description:Yapo2017- cAMP/PKA signalling in D1 dopamine receptor expressing medium-spiny neurons
This model is described in the article:
Detection of phasic dopamine
by D1 and D2 striatal medium spiny neurons.
Yapo C, Nair AG, Clement L, Castro
LR, Hellgren Kotaleski J, Vincent P.
J. Physiol. (Lond.) 2017 Aug; :
Abstract:
The phasic release of dopamine in the striatum determines
various aspects of reward and action selection, but the
dynamics of dopamine effect on intracellular signalling remains
poorly understood. We used genetically-encoded FRET biosensors
in striatal brain slices to quantify the effect of transient
dopamine on cAMP or PKA-dependent phosphorylation level, and
computational modelling to further explore the dynamics of this
signalling pathway. Medium-sized spiny neurons (MSNs), which
express either D1 or D2 dopamine receptors, responded to
dopamine by an increase or a decrease in cAMP, respectively.
Transient dopamine showed similar sub-micromolar efficacies on
cAMP in both D1 and D2 MSNs, thus challenging the commonly
accepted notion that dopamine efficacy is much higher on D2
than on D1 receptors. However, in D2 MSNs, the large decrease
in cAMP level triggered by transient dopamine did not translate
in a decrease in PKA-dependent phosphorylation level, owing to
the efficient inhibition of Protein Phosphatase 1 by DARPP-32.
Simulations further suggested that D2 MSNs can also operate in
a "tone-sensing" mode, allowing them to detect transient dips
in basal dopamine. Overall, our results show that D2 MSNs may
sense much more complex patterns of dopamine than previously
thought. This article is protected by copyright. All rights
reserved.
This model is hosted on
BioModels Database
and identified by:
MODEL1701170000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-08-16 | MODEL1701170000 | BioModels
Project description:Yapo2017 - A2AR/cAMP/PKA signalling in D2 dopamine receptor expressing medium-spiny neurons
This model is described in the article:
Detection of phasic dopamine
by D1 and D2 striatal medium spiny neurons.
Yapo C, Nair AG, Clement L, Castro
LR, Hellgren Kotaleski J, Vincent P.
J. Physiol. (Lond.) 2017 Aug; :
Abstract:
The phasic release of dopamine in the striatum determines
various aspects of reward and action selection, but the
dynamics of dopamine effect on intracellular signalling remains
poorly understood. We used genetically-encoded FRET biosensors
in striatal brain slices to quantify the effect of transient
dopamine on cAMP or PKA-dependent phosphorylation level, and
computational modelling to further explore the dynamics of this
signalling pathway. Medium-sized spiny neurons (MSNs), which
express either D1 or D2 dopamine receptors, responded to
dopamine by an increase or a decrease in cAMP, respectively.
Transient dopamine showed similar sub-micromolar efficacies on
cAMP in both D1 and D2 MSNs, thus challenging the commonly
accepted notion that dopamine efficacy is much higher on D2
than on D1 receptors. However, in D2 MSNs, the large decrease
in cAMP level triggered by transient dopamine did not translate
in a decrease in PKA-dependent phosphorylation level, owing to
the efficient inhibition of Protein Phosphatase 1 by DARPP-32.
Simulations further suggested that D2 MSNs can also operate in
a "tone-sensing" mode, allowing them to detect transient dips
in basal dopamine. Overall, our results show that D2 MSNs may
sense much more complex patterns of dopamine than previously
thought. This article is protected by copyright. All rights
reserved.
This model is hosted on
BioModels Database
and identified by:
MODEL1701170001.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-08-16 | MODEL1701170001 | BioModels