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Comparative gene expression profile of Ngn3-overexpressing cultured hippocampal neurons vs the corresponding control populations

ABSTRACT: Gene expression profiles of Ngn3-overexpressing cultured hippocampal neurons was compared to the profile of the corresponding control populations. (neurons expressing GFP). Neurogenin3, a proneural transcription factor controlled by Notch receptor, is involved in hippocampal neuron differentiation and synapses, but little is known about the molecular bases of Ngn3 activity in neurons. Microarray analysis indicated that overexpression of Ngn3 upregulated a number of genes related with cytoskeleton dynamics. One of then was Fmn1 whose protein is associated with actin and microtubule cytoskeleton. Overexpression of the isoform Fmn1-Ib in cultured hippocampal neurons induced an increase in the number of primary dendrites and in the number of glutamatergic synaptic inputs without affecting GABAergic synapses resulting in a modification in the balance between excitation and inhibition. The same changes were provoked by overexpression of Ngn3. In addition downregulation of Fmn1 by the use of Fmn1-siRNAs impaired such morphological and synaptic changes induced by Ngn3 overexpression in neurons. These results reveal a previously unknown involvement of Formin1 in dendritic and synaptic plasticity as a key protein in the Nng3 signaling pathway that contributes to understanding of molecular mechanisms of the neuronal differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE26911 | GEO | 2011/01/27

SECONDARY ACCESSION(S): PRJNA136173

REPOSITORIES: GEO

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Comparative gene expression profile of Ngn3-overexpressing cultured hippocampal neurons vs the corresponding control populations

Project description:Gene expression profiles of Ngn3-overexpressing cultured hippocampal neurons was compared to the profile of the corresponding control populations. (neurons expressing GFP). Neurogenin3, a proneural transcription factor controlled by Notch receptor, is involved in hippocampal neuron differentiation and synapses, but little is known about the molecular bases of Ngn3 activity in neurons. Microarray analysis indicated that overexpression of Ngn3 upregulated a number of genes related with cytoskeleton dynamics. One of then was Fmn1 whose protein is associated with actin and microtubule cytoskeleton. Overexpression of the isoform Fmn1-Ib in cultured hippocampal neurons induced an increase in the number of primary dendrites and in the number of glutamatergic synaptic inputs without affecting GABAergic synapses resulting in a modification in the balance between excitation and inhibition. The same changes were provoked by overexpression of Ngn3. In addition downregulation of Fmn1 by the use of Fmn1-siRNAs impaired such morphological and synaptic changes induced by Ngn3 overexpression in neurons. These results reveal a previously unknown involvement of Formin1 in dendritic and synaptic plasticity as a key protein in the Nng3 signaling pathway that contributes to understanding of molecular mechanisms of the neuronal differentiation. Cultured hippocampal neurons were transduced using Sindbis virus bearing myc-tagged Ngn3 or GFP as control. Cells were lysed and total RNA was extracted.Gene expression profiles were obtained for each sample and compared

2011-01-27 | E-GEOD-26911 | biostudies-arrayexpress

Activity-induced Nr4a1 regulates spine density and distribution pattern of excitatory synapses in pyramidal neurons

Project description:Excitatory synapses occur mainly on dendritic spines, and spine density is usually correlated with the strength of excitatory synaptic transmission. We report that Nr4a1, an activity-inducible gene encoding a nuclear receptor, regulates the density and distribution of dendritic spines in CA1 pyramidal neurons. Nr4a1 overexpression resulted in elimination of the majority of spines; however, postsynaptic densities were preserved on dendritic shafts, and the strength of excitatory synaptic transmission was unaffected, showing that excitatory synapses can be dissociated from spines. mRNA expression profiling studies suggest that Nr4a1-mediated transcriptional regulation of the actin cytoskeleton contributes to this effect. Under conditions of chronically elevated activity, when Nr4a1 was induced, Nr4a1 knockdown increased the density of spines and PSDs specifically at the distal ends of dendrites. Thus, Nr4a1 is a key component of an activity-induced transcriptional program that regulates the density and distribution of spines and synapses. After 10 days in culture, dissociated mouse hippocampal neurons in 6-well plates were infected with lentivirus expressing either Flag-Nr4a1 or GFP and incubated for 6 days to allow for transgene expression. Total RNA was then isolated using RNeasy Plus kit (QIAGEN). Samples passing an mRNA quality check proceeded to quantitative analysis on Agilent-026655 4x44 Mouse Microarrays.

2016-01-13 | E-GEOD-76805 | biostudies-arrayexpress

Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus

Project description:Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.

2020-12-14 | GSE161540 | GEO

Inducible Ngn3 Embryonic Stem Cells

Project description:Expression of the proendocrine gene neurogenin 3 (Ngn3) is required for the development of pancreatic islets. In order to better characterize the molecular events regulated by Ngn3 during development, we have determined the expression profile of differentiating murine embryonic stem cells (mESCs) uniformly induced to overexpress Ngn3. An ESC line was created that allows for the induction of Ngn3 by adding doxycycline (Dox) to the culture medium. Genome-wide microarray analysis was performed to identify genes regulated by Ngn3 in a variety of both undifferentiated and differentiated conditions. Characterization of pancreatic developmental markers during embryoid body (EB) formation revealed an optimum context for Ngn3 induction. Neuroendocrine genes including neurogenic differentiation 1 (NeuroD1) and single minded 1 (Sim1) were found to be significantly upregulated. Genes regulated by Ngn3 independent of the context were analyzed using systematic gene ontology tools and revealed Notch signaling as the most significantly regulated signaling pathway (p=0.009). This result is consistent with the hypothesis that Ngn3 expression makes the cell competent for Notch signaling to be activated and conversely, more sensitive to Notch signaling inhibition. Indeed, EBs induced to express Ngn3 were significantly more sensitive to gamma-secretase inhibitor-mediated Notch signaling inhibition (p<0.0001). Moreover, we find that Ngn3 induction in differentiating ESCs results in significant increases in insulin, glucagon, and somatostatin transcription. Keywords: Ngn3 induction, embryonic stem cell differentiation

2006-07-01 | GSE3653 | GEO

Identifying new interactors of NGN3 through IP-MS

Project description:NGN3 is a transcription factor whose transient expression during pancreatic development is vital for the generation of endocrine pancreatic cells, including beta cells. NGN3 stabilisation has been shown to induce exocrine-to-endocrine cell plasticity in the murine pancreas, making it a viable target for therapies aiming to replenish beta cells after immune-mediated destruction in type 1 diabetes patients. Here, we set out to identify new interactors of NGN3 that could play a role in its post-translational regulation. We transfected HEK293A cells with HA-tagged NGN3 and carried out immunoprecipitation of the HA-tag, followed by analysis of co-immunoprecipitated interactors via LC-MS/MS.

2023-03-27 | PXD033691 | Pride

S-SCAM is essential for synapse formation

Project description:Synapse formation is critical for the wiring of neural circuits in the developing brain. The synaptic scaffolding protein S-SCAM/MAGI-2 has important roles in the assembly of signaling complexes at postsynaptic densities. However, the role of S-SCAM in establishing the entire synapse is not known. Here, we report significant effects of RNAi-induced S-SCAM knockdown on the number of synapses in early stages of network development in vitro. In vivo knockdown during the first three postnatal weeks reduced the number of dendritic spines in the rat brain neocortex. Knockdown of S-SCAM in cultured hippocampal neurons severely reduced the clustering of both pre- and postsynaptic components. This included synaptic vesicle proteins, pre- and postsynaptic scaffolding proteins, and cell adhesion molecules, suggesting that entire synapses fail to form. Correspondingly, functional and morphological characteristics of developing neurons were affected by reducing S-SCAM protein levels: neurons displayed severely impaired synaptic transmission and reduced dendritic arborization. A next generation sequencing approach showed normal expression of housekeeping genes, but changes of expression levels in 39 synaptic signaling molecules in cultured neurons. These results indicate that S-SCAM mediates the recruitment of all key classes of synaptic molecules during synapse assembly and is critical for the development of neural circuits in the developing brain.

2023-10-02 | GSE228093 | GEO

Neurexin-3 defines synapse- and sex-dependent diversity of GABAergic inhibition in ventral subiculum

Project description:Ventral subiculum (vSUB) is integral to the regulation of stress and reward, however the intrinsic connectivity and synaptic properties of the inhibitory microcircuit are poorly understood. Neurexin-3 (Nrxn3) is highly expressed in hippocampal inhibitory neurons, but its function at inhibitory synapses has remained elusive. Using slice electrophysiology, imaging, and single-cell RNA sequencing, we identify multiple roles for Nrxn3 at GABAergic parvalbumin (PV) interneuron synapses made onto vSUB regular spiking (RS) and burst spiking (BS) principal neurons. Surprisingly, we found that intrinsic connectivity of vSUB and synaptic function of Nrxn3 in vSUB are sexually dimorphic. We reveal that vSUB PVs make preferential contact with RS neurons in males, but BS neurons in females. Furthermore, we determined that despite comparable Nrxn3 isoform expression in male and female PV neurons, Nrxn3 maintains synapse density at PV-RS synapses in males, but suppresses presynaptic release at the same synapses in females.

2021-12-09 | GSE171793 | GEO

Activity-induced Nr4a1 regulates spine density and distribution pattern of excitatory synapses in pyramidal neurons

2016-01-13 | GSE76805 | GEO

Induced overexpression of Pdx1 and Ngn3 in a mouse ES cell-derived endoderm population induces pancreatic differentiation

Project description:Induced overexpression of Pdx1 in activin-induced endoderm population resulted in the upregulation of pancreas-related genes such as insulin 1 and 2 at day 20. To enhance the developmental progression from the pancreatic bud to the formation of the endocrine lineages, we next expressed neurogenin3 (Ngn3) together with Pdx-1. Induced overexpression of Pdx1 together with Ngn3 dramatically increased Insulin 1 mRNA by day 9 differentiation. The levels of insulin 1 mRNA present in the induced EBs represented approximately 100 % of that found in insulinoma cell line, betaTC6. We also confirmed insulin and C-peptide staining by immunohistochemistry. These cells process and secrete insulin and respond to various insulin secretagogues. These inductive effects were restricted to c-kit+ endoderm enriched EB-derived populations suggesting that Pdx1/Ngn3 functions at the level of pancreatic specification of endoderm in this model. Microarray analysis showed that Pdx1/Ngn3 regulated the expression of a broad spectrum of pancreatic endocrine cell-related genes.

2010-08-24 | GSE23752 | GEO

Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons

Project description:The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change of function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.

2019-06-27 | GSE131428 | GEO

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