Switching of RNA splicing regulators in immature neuroblasts during adult neurogenesis

eLife, 2023 · DOI: https://doi.org/10.7554/eLife.87083 · Published: November 22, 2023

Simple Explanation

The study investigates how new neurons are made in the adult mouse brain, specifically in the subventricular zone (SVZ). It identifies a specific population of cells called immature neuroblasts (iNBs) that are at a transition stage between progenitor cells and mature neurons. Researchers found that iNBs have characteristics of both neural progenitors and neuroblasts, and they also possess regenerative capabilities. These iNBs undergo changes in the expression of splicing regulators, which are important for their differentiation into migrating neuroblasts (mNBs). The findings suggest a revision of the current model of adult neurogenesis, highlighting the role of iNBs as a crucial intermediate stage with potential for regenerative therapy in brain damage.

Study Duration

5 weeks (transplant experiments)

Participants

Adult male C57BL/6 J, β−actin:eGFP, and DCX-CreERT2::CAG-CAT-eGFP mice

Evidence Level

Not specified

Key Findings

1
iNBs are a molecularly distinct class of SVZ cells, exhibiting features of both neural progenitors and neuroblasts, while retaining regenerative capacity and plasticity.
2
There are sequential molecular switches occurring in iNBs before their final differentiation into migrating neuroblasts, including changes in the expression of RNA splicing regulators.
3
s-iNB correspond to specific SVZ cell clusters identified by single-cell RNA sequencing (scRNAseq), matching with clusters termed ‘Mitosis’ and ‘Mitotic TAP’ in previous studies.

Research Summary

This study combines transcriptomic profiling using DNA microarrays and large-scale scRNAseq to analyze the molecular and cellular changes during SVZ neurogenesis. It identifies and characterizes immature neuroblasts (iNBs) as an abundant population of cycling progenitors. The research demonstrates that iNBs are more advanced toward neuronal differentiation than transit-amplifying progenitors (TAP) but retain stem cell properties unlike migrating neuroblasts (mNBs). Major splicing regulations in iNBs are found to be critical for their final commitment to the neuronal fate. The study also provides insights into the sequential regeneration of neurogenic cell clusters after brain irradiation, establishing a hierarchical ordering of these clusters and highlighting the progressive molecular changes leading to the differentiation into migrating neuroblasts.

Practical Implications

Regenerative Medicine

iNB cells, with their plasticity and multipotency, could be a new target for regenerative medicine, especially in the context of brain damage.

Therapeutic Targeting

Further characterization of iNB cells and the RNA splicing regulators involved may offer potential therapeutic targeting strategies in various brain pathologies.

Understanding Neurogenesis

The revision of the current model of SVZ neurogenesis with the inclusion of iNBs provides a more comprehensive understanding of the transitions during neurogenesis.

Study Limitations

1
The evidence does not fully support the claims, leaving it currently incomplete.
2
The proposed role of RNA splicing in neuronal differentiation, though interesting, remains unexplored and would benefit significantly from targeted gene manipulation studies.
3
Our study has been performed on cells collected from the SVZ the LWs of the ventricles of young adult mice.

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