bioRxiv : the preprint server for biologyOct 3, 2025

Understanding Gene Networks That Control Human Brain Cell Development

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 3, 2026

Abstract

The study identifies multiple transcription factors (TFs) that may regulate cortical neurogenesis and lineage progression in human neural stem cells.

A human primary culture system was established to assess cell fate dynamics during neurogenesis.
Single cell CRISPR interference screening of 44 active TFs revealed novel roles in influencing neural differentiation.
Some identified TFs may repress neural differentiation and regulate the plasticity of radial glia lineage across developmental stages.
Convergent effector genes associated with neurodevelopmental and neuropsychiatric disorders were identified downstream of these TFs.
Conserved mechanisms of radial glia lineage plasticity were observed across primate species.

Simplified

Human cortical neurogenesis involves conserved and specialized developmental processes during a restricted window of prenatal development. Radial glia (RG) neural stem cells shape cortical cell diversity by giving rise to excitatory neurons, oligodendrocytes, and astrocytes, as well as olfactory bulb interneurons (INs) and a recently characterized population of cortical INs. Complex genetic programs orchestrated by transcription factor (TF) circuits govern the balance between self-renewal and differentiation, and between different cell fates. Despite progress in measuring gene regulatory network activity during human cortical development, functional studies are required to evaluate the roles of TFs and effector genes in human RG lineage progression. Here we establish a human primary culture system that allows sensitive discrimination of cell fate dynamics and apply single cell clustered regularly interspaced short palindromic repeats interference (CRISPRi) screeningto examine the transcriptional and cell fate consequences of 44 TFs active during cortical neurogenesis. We identified multiple TFs, with novel roles in cortical neurogenesis, includingpreviously uncharacterized, that represses neural differentiation andandthat have opposing roles in regulating RG lineage plasticity and progression across developmental stages. We also uncovered convergent effector genes downstream of multiple TFs enriched in neurodevelopmental and neuropsychiatric disorders and observed conserved mechanisms of RG lineage plasticity across primates. We further uncovered a postmitotic role forin safeguarding IN subtype specification through repressing. Our study provides a framework for dissecting regulatory networks driving cell fate consequences during human neurogenesis. 1,2 3-8 9-12 13,14ZNF219, NR2E1ARX ARX LMO1

Funding

Competing interests

Competing interests The authors declare no competing interests.

PubMed

Understanding Gene Networks That Control Human Brain Cell Development

Abstract

Funding

Competing interests

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Abstract

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

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Recent issues from the crispr gene editing brief