Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJDB20400 | ENA |
REPOSITORIES: ENA
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Project description:Experience and activity-dependent transcription is a candidate mechanism to mediate development and refinement of specific cortical circuits. Here we provide evidence that the activity-dependent transcription factor Myocyte-Enhancer Factor 2C (MEF2C) is required in both presynaptic layer 4 (L4) and postsynaptic L2/3 somatosensory (S1) cortical neurons for development of their synaptic connection. In contrast, synaptic inputs from local L2/3, contralateral S1, or ipsilateral frontal/motor cortex are unaffected by postsynaptic Mef2c deletion in L2/3 neurons. Postsynaptic MEF2C is required for L4 to L2/3 synapse function during, but not after, an early postnatal, experience-dependent period. Furthermore, homozygous and heterozygous Mef2c deletion in presynaptic L4 neurons weakens L4 to L2/3 excitatory synaptic inputs by decreasing presynaptic release probability. Our results suggested that experience or activity-dependent transcriptional activation of MEF2C promotes development of L4→L2/3 synapses. In support of this idea, expression of transcriptionally active MEF2C (MEF2C-VP16) rescued weak L4 to L2/3 synaptic strength in sensory deprived mice. Consistent with a presynaptic function for MEF2C, we find that MEF2C regulates the activity-dependent expression of many presynaptic assembly genes, including transsynaptic cell adhesion proteins and regulators of neurotransmitter release. This work provides mechanistic insight into the experience-dependent development of specific cortical circuits.
2025-01-17 | GSE253629 | GEO
Project description:The emergence of functional cerebellar circuits is heavily influenced by activity-dependent processes. However, the contribution of intrinsic Purkinje cell activity to cerebellar development remains less understood. Here, we demonstrate that before synaptic networks mature, Purkinje cell intrinsic activity is essential for regulating dendritic growth, establishing connections with cerebellar nuclei, and ensuring proper cerebellar function. Disrupting this activity during the postnatal period impairs motor function, with earlier perturbations causing more severe deficits. Importantly, only early developmental disruptions lead to pronounced defects in cellular morphology, highlighting key temporal windows for dendritic growth and maturation. Transcriptomic analyses reveal that early intrinsic activity drives the expression of activity-dependent genes, including Prkcg and Car8, which are essential for dendritic development. Our findings emphasize the importance of temporally regulated intrinsic activity in Purkinje cells in guiding cerebellar circuit development, providing a potential unifying mechanism underlying cerebellum-associated disorders.
2026-02-03 | GSE294208 | GEO
Project description:In this study, we identified active enhancers in the mouse cerebellum at embryonic and postnatal stages establishing the first catalog of enhancers active during embryonic cerebellum development. The majority of cerebellar enhancers have dynamic activity between embryonic and postnatal development. Cerebellar enhancers were enriched for neural transcription factor binding sites with temporally specific expression. Putative gene targets displayed spatially restricted expression patterns, indicating cell-type specific expression regulation. Functional analysis of target genes indicated that enhancers regulate processes spanning several developmental epochs such as specification, differentiation and maturation. We use these analyses to discover one novel regulator and one novel marker of cerebellar development: Bhlhe22 and Pax3, respectively. We identified an enrichment of de novo mutations and variants associated with autism spectrum disorder in cerebellar enhancers. Our study provides insight into the dynamics of gene expression regulation by enhancers in the developing brain and delivers a rich resource of novel gene-enhancer associations providing a basis for future in-depth studies in the cerebellum.
2021-09-15 | GSE183697 | GEO
Project description:Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelop- mental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MeCP2 causes miswiring of neural circuits due to defects in the brain’s capacity to respond to changes in neuronal activity and sensory experience. Here, we show that MeCP2 is phosphorylated at four residues in the brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from the synapse refinement defect previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period.
2023-10-15 | GSE245022 | GEO
Project description:Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelop- mental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MeCP2 causes miswiring of neural circuits due to defects in the brain’s capacity to respond to changes in neuronal activity and sensory experience. Here, we show that MeCP2 is phosphorylated at four residues in the brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from the synapse refinement defect previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period.
2023-10-15 | GSE245021 | GEO
Project description:Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelop- mental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MeCP2 causes miswiring of neural circuits due to defects in the brain’s capacity to respond to changes in neuronal activity and sensory experience. Here, we show that MeCP2 is phosphorylated at four residues in the brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from the synapse refinement defect previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period.
2023-10-15 | GSE245024 | GEO
Project description:The histone H3 lysine 27 (H3K27) demethylase Kdm6b (Jmjd3) can promote cellular differentiation, however its physiological functions in neurons remain to be fully determined. We studied the expression and function of Kdm6b in differentiating granule neurons of the developing postnatal mouse cerebellum. At postnatal day 7, Kdm6b is expressed throughout the layers of the developing cerebellar cortex, but its expression is upregulated in newborn cerebellar granule neurons (CGNs). Atoh1-Cre mediated conditional knockout of Kdm6b in CGN precursors either alone or in combination with Kdm6a did not disturb the gross morphological development of the cerebellum. Furthermore, RNAi-mediated knockdown of Kdm6b in cultured CGN precursors did not alter the induced expression of early neuronal marker genes upon cell cycle exit. By contrast, knockdown of Kdm6b significantly impaired the induction of a mature neuronal gene expression program, which includes gene products required for functional synapse maturation. Loss of Kdm6b also impaired the ability of Brain-Derived Neurotrophic Factor (BDNF) to induce expression of Grin2c and Tiam1 in maturing CGNs. Taken together, these data reveal a previously unknown role for Kdm6b in the postmitotic stages of CGN maturation and suggest that Kdm6b may work, at least in part, by a transcriptional mechanism that promotes gene sensitivity to regulation by BDNF.
2017-11-20 | GSE106120 | GEO
Project description:The endoribonuclease, Dicer, is indispensible for generating the majority of mature microRNAs (miRNAs), which are posttranscriptional regulators of gene expression involved in a wide range of developmental and pathological processes in mammalian central nervous system. While functions of Dicer-dependent miRNA pathways in neurons and oligodendrocytes have been extensively investigated, little is known about the role of Dicer in astrocytes. Here we report the effect of Cre-loxP mediated conditional deletion of Dicer selectively from postnatal astroglia on brain development. Dicer-deficient mice exhibited normal motor development and neurological morphology prior to postnatal week 5. Thereafter mutant mice invariably developed a rapidly fulminant neurological decline characterized by ataxia, severe progressive cerebellar degeneration, seizures, uncontrollable movements and premature death by postnatal week 9-10. Integrated transcription profiling, histological and functional analyses of cerebella showed that deletion of Dicer in cerebellar astrocytes altered the transcriptome of astrocytes to be more similar to an immature or reactive-like state prior to the onset of neurological symptoms or morphological changes. As a result, critical and mature astrocytic functions including glutamate uptake and antioxidant pathways were substantially impaired, leading to massive apoptosis of cerebellar granule cells and degeneration of Purkinje cells. Collectively, our study demonstrates the critical involvement of Dicer in normal astrocyte maturation and maintenance. Our findings also reveal non-cell autonomous roles of astrocytic Dicer-dependent pathways in regulating proper neuronal functions and implicate that loss of or dysregulation of astrocytic Dicer-dependent pathways may be involved in neurodegeneration and other neurological disorders. Four replicate experiments using samples derived from biologically independent pairs of control (mGfap-Cre; Dicer +/flox) and Dicer mutant (mGfap-Cre; Dicer flox/flox) littermate mice (postnatal day 30) were performed with a dye-swap experimental design.
2011-05-10 | E-GEOD-28589 | biostudies-arrayexpress
Project description:Synapse formation and elimination are two crucial processes that concurrently take place in the developing brain. Astrocytes and microglia have been shown to control both processes. However, it is largely unknown how these two major glial cell types of the central nervous system (CNS) communicate to balance synapse formation and elimination. Astrocytes secrete a synaptogenic protein called Hevin/SPARCL1, which induces the formation and plasticity of thalamocortical synapses in the mouse visual cortex. Hevin does so by physically localizing to synaptic clefts and bridging the thalamic axon/cortical dendrite via its interactions with presynaptic Neurexin1a and postsynaptic Neuroligin1b. Here, we found that in addition to this synaptogenic function, Hevin directly signals to microglia cells by interacting with Toll-like Receptors (TLRs) TLR4 and TLR2. This signaling occurs when Hevin is proteolytically cleaved producing an active C-terminal fragment. This fragment is sufficient to upregulate TLR2 expression in microglia and increase microglia phagocytic activity in vivo. This signaling is required for proper refinement of thalamocortical synapses in early postnatal development and for early life ocular dominance plasticity.
2025-12-31 | GSE259420 | GEO
Project description:Ongoing neuronal activity during development and plasticity acts to refine synaptic connections and contributes to the induction of plasticity and ultimately long term memory storage. Activity-dependent post-transcriptional control of mRNAs occurs through transport to axonal and dendritic compartments, local translation, and mRNA stability. We have identified a mechanism that contributes to activity-dependent regulation of mRNA stability during synaptic plasticity. In this study we demonstrate rapid, post-transtriptional control over process-enriched mRNAs by neuronal activity. Systematic analysis of the 3'-UTRs of destablized transcripts, identifies enrichment in sequence motifs corresponding to miRNA binding sites. The miRNAs that were identified, miR-326-3p/miR-330-5p, miR-485-5p, miR-666-3p, and miR-761 are predicted to regulate networks of genes important in plasticity and development. We find that these miRNAs are developmentally regulated in the hippocampus, many increasing by postnatal day 14. We further show that miR-485-5p controls NGF-induced neurite outgrowth in PC12 cells, tau expression, and axonal development in hippocampal neurons. miRNAs can function at the synapse to rapidly control and affect short- and long-term changes at the synapse. These processes likely occur during refinement of synaptic connections and contribute to the induction of plasticity and learning and memory. 12 hippocampal cell culture samples analysed, 3 coverslips pooled per sample. Treatments are as follows: Block: an inhibitor cocktail containing 50 µM D-APV, 40 µM CNQX, and 100 nM TTX for 3 hrs Activity: 50 µM bicuculline (BiC)/500 µM 4-Aminopyridine ActD: 25 µM actinomycin D
2014-03-12 | E-GEOD-55777 | biostudies-arrayexpress