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Transcription factor Sp9 is a negative regulator of D1-type MSN development [RNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE202550 | GEO | 2022/07/06

REPOSITORIES: GEO

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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.

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.

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Transcription factor Sp9 is a negative regulator of D1-type MSN development [RNA-Seq]

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