Distinct differentiation trajectories leave lasting impacts on gene regulation and function of V2a interneurons

bioRxiv preprint, 2024 · DOI: https://doi.org/10.1101/2024.12.03.626573 · Published: December 6, 2024

Regenerative Medicine Neurology Genetics

Simple Explanation

During development, cells with similar characteristics can arise from different origins. This study examines V2a neurons, which are important for motor function and can be derived from different progenitor cells. The researchers differentiated V2a neurons from human stem cells using methods that mimic either anterior or posterior development. They then compared the resulting neurons using multiomic analysis. The study found that the origin of V2a neurons significantly impacts their gene expression, chromatin accessibility, and network activity, emphasizing the importance of developmental context in creating authentic cell identities.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Not specified

Key Findings

1
Distinct progenitor origins (NEP vs. NMP) lead to differences in gene expression and chromatin accessibility in V2a neurons, even under identical differentiation conditions.
2
NMP-derived V2a neurons exhibit more rapid establishment of synchronous network activity compared to NEP-derived neurons.
3
Transcription factor-induced neurons, while superficially similar, lack the stable chromatin modifications and gene regulatory networks of developmentally derived V2a neurons.

Research Summary

The study investigates how different developmental origins shape the properties of V2a neurons, excitatory interneurons important for motor function, by differentiating them from hPSC-derived progenitors with distinct anteroposterior identities. Single-nucleus multiomic analysis revealed lineage-specific transcription factor motifs and differentially expressed genes related to axon growth and calcium handling. The study identified CREB5 and TCF7L2 as regulators specific to posterior identities, underscoring the critical role of lineage origins in determining cell states and functions.

Practical Implications

Therapeutic Potential

Understanding the functional differences between NEP and NMP-derived V2a neurons may allow for the development of more effective cell therapies for spinal cord injury.

Directed Differentiation Strategies

The study highlights the need for developmentally accurate directed differentiation strategies to generate relevant and authentic cell types for developmental and disease modeling.

Drug Discovery

The identification of CREB5 and TCF7L2 as key regulators could lead to new drug targets for modulating neurodevelopmental pathways.

Study Limitations

1
Multiomic analysis captures only a single time point, limiting the ability to determine whether lineage identity is retained over time.
2
snATAC-seq reveals enriched motifs, but ChIP-seq is needed to pinpoint TF binding at specific loci.
3
Observed activity patterns are confounded by mixed populations, necessitating targeted drug perturbations or sorted cultures to resolve these effects.

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