An increase in ROS is required for repair of the neonatal cerebellum
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ABSTRACT:
PROVIDER: PRJNA1121249 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29319651_1.fastq.gz | Fastqsanger.gz | |||
| SRR29319651_2.fastq.gz | Fastqsanger.gz | |||
| SRR29319652_1.fastq.gz | Fastqsanger.gz | |||
| SRR29319652_2.fastq.gz | Fastqsanger.gz | |||
| SRR29319653_1.fastq.gz | Fastqsanger.gz |
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Project description:The neonatal mouse cerebellum shows remarkable regenerative potential upon injury at birth. Nestin-expressing progenitors (NEPs) undergo adaptive reprogramming to replenish the lost granule cell progenitors. Here, we investigate how the injury microenvironment affects NEPs’ regenerative potential and adaptive reprogramming. Single cell transcriptomic and bulk chromatin accessibility analyses of the NEPs from control and injured neonatal cerebella show a temporary increase in mechanisms involved in the response to reactive oxygen species (ROS), a known damage-associated molecular pattern. Analysis of ROS levels also confirms a temporary increase in ROS levels upon injury at postanal day 1, 1-2 days after injury, overlapping with the induction in cell death in the cerebellum. Using a transgenic mouse model that overexpresses mitochondrial catalase (mCAT) and reduces ROS levels globally, we showed that the regenerative potential of NEPs decreases upon injury to the granule cell progenitors at birth and the repair is impaired. Finally, we demonstrated that microglia are involved in adaptive reprogramming by regulating NEP migration to the external granule layer, the site of injury. Collectively, our results highlight that the changes in the tissue microenvironment such as an increase in the ROS levels are required for the adaptative reprogramming of NEPs upon injury to the granule cell progenitors at birth, highlighting the instructive roles of microenvironmental signals during regeneration in the neonatal brain.
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Project description:The neonatal mouse cerebellum shows remarkable regenerative potential upon injury at birth, wherein a subset of Nestin-expressing progenitors (NEPs) undergoes adaptive reprogramming to replenish granule cell progenitors that die. Here, we investigate how the microenvironment of the injured cerebellum changes upon injury and contributes to the regenerative potential of normally gliogenic-NEPs and their adaptive reprogramming. Single cell transcriptomic and bulk chromatin accessibility analyses of the NEPs from injured neonatal cerebella compared to controls show a temporary increase in cellular processes involved in responding to reactive oxygen species (ROS), a known damage-associated molecular pattern. Analysis of ROS levels in cerebellar tissue confirm a transient increased one day after injury at postanal day 1, overlapping with the peak cell death in the cerebellum. In a transgenic mouse line that ubiquitously overexpresses human mitochondrial catalase (mCAT), ROS is reduced 1 day after injury to the granule cell progenitors, and we demonstrate that several steps in the regenerative process of NEPs are curtailed leading to reduced cerebellar growth. We also provide preliminary evidence that microglia are involved in one step of adaptive reprogramming by regulating NEP replenishment of the granule cell precursors. Collectively, our results highlight that changes in the tissue microenvironment regulate multiple steps in adaptative reprogramming of NEPs upon death of cerebellar granule cell progenitors at birth, highlighting the instructive roles of microenvironmental signals during regeneration of the neonatal brain.
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