S-SCAM is essential for synapse formation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA948026 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23949800.fastq.gz | Fastqsanger.gz | |||
| SRR23949801.fastq.gz | Fastqsanger.gz | |||
| SRR23949802.fastq.gz | Fastqsanger.gz | |||
| SRR23949803.fastq.gz | Fastqsanger.gz | |||
| SRR23949804.fastq.gz | Fastqsanger.gz |
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Project description:Synapses are asymmetric junctions between presynaptic and postsynaptic neurons that mediate information transfer in the brain. The proper formation of functional synapses is crucial for synaptic transmission and brain function. However, how neurons initially recognize each other to form synapses remain to be elucidated. Here, we performed single-cell RNA sequencing of the cultured hippocampal cells on the critical time points during synapse development. . We first built comprehensive single-cell transcriptomic atlas of hippocampus undergoing synapse formation. Furthermore, we focused on neurons, and systematically analyzed temporal dynamic functional transcription factors hubs.. We identified that transcription factors, such as EGR family genes, AP-1 family genes, NeuroD family genes, NF1 family genes, may act as key regulators of synapse formation. Besides, we provided the resources of increased membrane and secretory proteins associated with synapse formation, which including previously reported synapse formation genes, Nlgn3, Nectin1, Dag1, Snap25, and the newly identified potential genes, Tmem65, Grm5, Olfm1, Timp3. Finally, we analyzed the changes of cell communication signaling pathways in neurons before and after synapse formation, and identified several important signaling pathways, including NRXN, NCAM, BMP, NEGR, and so on. Collectively, our work provided a holistic view of the molecular dynamics of the hippocampal synapse formation.
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Project description:Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders. Wolfram syndrome (WS) mainly caused by WFS1 deficiency is a monogenic genetic disease manifested by severe psychiatric disorders. Due to athe lack of proper human disease models, the underlying mechanism is poorly understood. Particularly, whether and how WFS1 deficiency affects synapse formation remain elusive. By mirroring the complexity of human brain development with cerebral organoids derived from human embryonic stem cells (hESCs) harboring WFS1 loss of function (LOF), we found that WFS1-deficient cerebral organoids not only recapitulated the neuronal loss phenotype in WS patients, but also exhibited significantly impaired synapse formation associated with reduced astrocytes, suggesting a defective structural basis for psychiatric disorders elicited by WFS1 deficiency. To further unravel the complexity of interplay between neurons and astrocytes, each neural cell type was respectively differentiated from hESCs harboring WFS1 LOF. WFS1 deficiency in neurons autonomously delayed neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impaired neurite outgrowth and reduced synapse formation associated with elevated cytosolic calcium. Interestingly, WFS1 deficiency in astrocytes decreased the expression of glutamate transporter EAAT2 and compromised glutamate uptake, causing reduced neurite outgrowth with increased cytosolic calcium when co-cultured with wildtype (WT) neurons, highlighting pathogenic role of WFS1-deficient astrocytes. Importantly, restoring EAAT2 expression in astrocytes by riluzole treatment significantly alleviated reduced neurite outgrowth phenotype in WT neurons co-cultured with WFS1-deficient astrocytes. Altogether, our study provides novel insights into how WFS1 deficiency affects neurite outgrowth and synapse formation, potentially contributing to predisposition of psychiatric disorders, and offers a potential strategy of therapy.
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Project description:How synapses are assembled and specified in brain is incompletely understood. Latrophilin-3, a postsynaptic adhesion-GPCR, mediates Schaffer-collateral synapse formation in the hippocampus but the mechanisms involved remained unclear. Here we show that Latrophilin-3 organizes synapses by a convergent dual-pathway mechanism by which Latrophilin-3 simultaneously activates GaS/cAMP-signaling and recruits phase-separated postsynaptic protein scaffolds. We found that cell type-specific alternative splicing of Latrophilin-3 controls its G protein coupling mode, resulting in Latrophilin-3 variants that predominantly signal via Gas and cAMP or via Gα12/13. A CRISPR-mediated genetic switch of Latrophilin-3 alternative splicing from a GaS- to a Gα12/13-coupled mode impaired synaptic connectivity similar to the overall deletion of Latrophilin-3, suggesting that GaS/cAMP-signaling by Latrophilin-3 splice variants mediates synapse formation. Moreover, GaS- but not Gα12/13-coupled splice variants of Latrophilin-3 recruit phase-transitioned postsynaptic protein scaffolds that are clustered by binding of presynaptic Latrophilin-3 ligands. Strikingly, neuronal activity promotes alternative splicing of the synaptogenic variant of Latrophilin-3, thereby enhancing synaptic connectivity. Together, these data suggest that activity-dependent alternative splicing of a key synaptic adhesion molecule controls synapse formation by parallel activation of two convergent pathways, GaS/cAMP signaling and the phase separation of postsynaptic protein scaffolds.
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