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Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling [Smad1cKOvsctrl_RNAseq]

ABSTRACT: Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific disruption of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation – inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.

ORGANISM(S): Mus musculus

PROVIDER: GSE255563 | GEO | 2024/02/16

REPOSITORIES: GEO

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Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling [RNA-seq]

Project description:Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific disruption of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation – inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.

2024-02-16 | GSE255562 | GEO

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling

2024-02-16 | GSE255466 | GEO

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling [ChIP-seq]

2024-02-16 | GSE255587 | GEO

RNA-seq of PV+ interneurons in WT and Cox6a2-/- mice to unravel the molecular signaling that contributes to the increase in oxidative stress and metabolic dysregulation following Cox6a2 knockout.

Project description:Gamma-aminobutyric acid-containing (GABAergic) interneurons are the major source of inhibition in the mammalian brain. They control the output of principal neurons, shaping brain oscillations and maintaining excitation/inhibition balance. PV+ interneurons play a major role in the regulation of the excitatory/inhibitory balance in the cortex. One gene of the oxidative phosphorylation machinery shows particularly specific expression in PV+ interneurons, Cox6a2. The gene codes for the isoform 2 of the subunit Cox6a in cytochrome c oxidase, also known as complex IV (CIV), of oxidative phosphorylation. Cox6a2 had been shown to regulate the generation of energy in the heart and skeletal muscle to meet the high energy demands. To unravel the molecular signaling that contributes to the increase in oxidative stress and metabolic dysregulation following Cox6a2 knockout, we sorted PV+ interneurons from wild-type and Cox6a2-/- mice using the PV-EGFP transgenic mouse line and compared the neuronal transcriptome between the two phenotypes by RNA sequencing. We noted significant transcriptional changes in Cox6a2-/- PV+ interneurons relative to WT. Thus, we found deregulated expression of a number of genes that are involved in synaptic transmission and cellular metabolism.

2020-01-01 | E-MTAB-7879 | biostudies-arrayexpress

Single-cell transcriptomics reveals conserved regulatory networks in human and mouse interneuron development

Project description:Inhibitory GABAergic interneurons originate in the embryonic medial ganglionic eminence (MGE) and control network activity in the neocortex. Dysfunction of these cells is believed to lead to runaway excitation underlying seizure-based neurological disorders such as epilepsy, autism and schizophrenia. Despite their importance in heath and disease, our knowledge about the development of this diverse neuronal population remains incomplete. Here we conducted single cell RNA sequencing (scRNA-seq) of human fetal MGE from 10 to 15 weeks post conception. These MGE tissues are composed of largely cycling progenitors and immature post-mitotic interneurons with characteristic regional marker expression. Analysis of integrated human and mouse MGE data revealed species conserved transcriptomic profiles and regulatory program. Moreover, we identified novel candidate transcription regulators for human interneuron differentiation. These findings provide a framework for in vitro modelling of interneuron development and strategy for potentially enhance interneurons production from human pluripotent stem cells.

2023-04-29 | GSE230467 | GEO

Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks

Project description:Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from humaninduced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.

2021-05-17 | GSE144197 | GEO

Epigenetic regulation of Bmp2 and Smad6 in Ras-induced senescence

Project description:Epigenetically silenced Ink4a-Arf locus is activated by loss of H3K27me3 in cellular senescence, where secreted factor expression is also involved. Here we analyzed epigenome and transcriptome alteration during Ras-induced senescence using mouse embryonic fibroblast (MEF). Seventeen genes with H3K27me3 loss and H3K4me3 gain showed marked upregulation, including p16Ink4a and Bmp2, a secreted factor for BMP/SMAD signal. Smad6, specific BMP/SMAD pathway inhibitor, was identified as the only one gene showing de novo H3K27 trimethylation with H3K4me3, resulting in strong repression. Ras-activated cells senesced with SMAD1/5/8 phosphorylation, and they escaped from senescence with decreased SMAD1/5/8 phosphorylation when introducing Smad6 or knocking-down Bmp2.

2011-12-22 | GSE18125 | GEO

Neo-adjuvant Simvastatin therapy in colorectal cancer

Project description:Primary objectives: To ascertain whether orally delivered Simvastatin affects levels of apoptosis, proliferation and bone morphogenetic protein pathway activation in colorectal cancer in humans. Primary endpoints: Levels of BMP2 and 4 and phospho-Smad1 in surgical resection specimens.levels of apoptosis and proliferation in surgical resection specimenslevels of angiogenesis in surgical resection specimens

| 2521817 | ecrin-mdr-crc

Gene expression profiling of human endometrial stromal cells transduced with BMP2- and WNT4-adenovirus.

Project description:Our previous studies have shown that bone morphogenetic protein 2 (BMP2), a morphogen belonging to the TGFβ superfamily, is markedly induced in human primary endometrial stromal cells (HESC) as they undergo differentiation in response to steroid hormones and cAMP. WNT4 is a downstream target of BMP2 regulation in these cells. To identify the common downstream targets of BMP2 and WNT4 in human endometrial stromal cells, we performed gene expression profling of human ensometrial stromal cell transduced with BMP2 or WNT4 adenovirus. Gene expression profiling revealed that FOXO1, a forkhead family transcription factor and a known regulator of HESC differentiation, is a common downstream mediator of both BMP2 and WNT4 signaling. These studies uncovered a linear pathway involving BMP2, WNT4, and FOXO1 that operates in human endometrium to critically control decidualization.

2013-02-08 | GSE39949 | GEO

Transcriptome of MEFs with BMP2 and DNA damage reagents

Project description:The tightly controlled BMP-Smad1 pathway is essential for embryonic development and postnatal tissue homeostasis. Dysfunction of BMP-Smad1 signaling also leads to tumor development such as juvenile polyposis and Cowden syndromes and various tumors in mouse models, with unknown pathological mechanisms. Here we establish a link between the BMP-Smad pathway and the prominent tumor suppressor Atm-p53 pathway. We identify activated nuclear Smad1 as an Atm substrate under genotoxic stress. Atm-mediated Smad1 S239 phosphorylation disrupts Smad1 interaction with protein phosphatase PPM1A and enhances Smad1 activation and up-regulation, which not only turns on target genes including Cdk1nc but also interacts with p53 and inhibits Mdm2-mediated p53 ubiquitination, leading to p53 stabilization. Functionally, Smad1 acts like a tumor suppressor in DNA damage response, cell transformation and tumorigenesis in a p53-dependent manner. Sequencing of the gastric cancer samples revealed that Smad1 is frequently mutated, with S239 as mutational hotspot. This study thus establishes the BMP-Smad1 pathway as an integral part of DNA damage response, which can suppresses tumorigenesis via p53. Transformed MEFs (Smad1f/f, Smad1f/f Cre) treated with 50ng/ml BMP2, 1 ug/ml doxorubincin, or both for different periods of time. The mRNA levels of all genes were compared using microarray analysis.

2012-12-31 | E-GEOD-36843 | biostudies-arrayexpress

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