Postnatal neuronal Bace1 deletion impairs neuroblast and oligodendrocyte maturation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA901474 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22284421.fastq.gz | Fastqsanger.gz | |||
| SRR22284422.fastq.gz | Fastqsanger.gz | |||
| SRR22284423.fastq.gz | Fastqsanger.gz | |||
| SRR22284424.fastq.gz | Fastqsanger.gz | |||
| SRR22284425.fastq.gz | Fastqsanger.gz |
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Project description:We aim to understand the effect of postnatal neuronal deletion of Bace1 on the transcriptome of the hippocampus
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Project description:Beta amyloid cleaving enzyme 1 (BACE1) is largely expressed by neurons and is the sole β-secretase for initiating the production of neuronal β-amyloid peptides (Aβ). To fully understand the physiological functions of neuronal BACE1, we used mouse genetic approach coupled with unbiased single nucleus RNA sequencing (snRNAseq) to investigate how targeted deletion of Bace1 in neurons, driven by Thy-1-Cre recombinase, would affect functions in the nervous system. Our transcriptome results revealed that BACE1 is essential for maturation of neural precursor cells and oligodendrocytes in mice. RNA velocity analysis confirmed deficit in the trajectory of neuroblasts in reaching the immature granule neuron state in young Bace1fl/fl; Thy1-cre mice. Further analysis of differential gene expression indicated changes in genes important for SNARE signaling, tight junction signaling, synaptogenesis and insulin secretion pathways. Morphological studies revealed a hypomyelination in Bace1fl/fl;Thy1-cre sciatic nerves, but no detectable myelination changes in the corpus callosum, despite clear reduction in myelination proteins in the brain. Functional studies showed reduction in long-term potential, defects in synaptogenesis and learning behavioral. Altogether, our results show that neuronal BACE1 is critical for optimal development of central and peripheral nervous system, and inhibition of neuronal BACE1 will result in deficits in synaptic functions and cognitive behaviors.
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Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
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