eLifeOct 20, 2026

Using CRISPRi to reveal a gene activity switch between KLF activators and repressors in the developing thinking areas of the brain

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Updated Oct 21, 2026

Abstract

A shift in expression from KLF activators to repressors occurs during the first postnatal month in mouse neocortex.

Neurons in the mouse neocortex experience significant morphological and physiological changes during the first month after birth.
The Krüppel-like factor (KLF) family of transcription factors may play a crucial role in regulating the maturation of neonatally expressed genes.
KLF activators (Klf6, Klf7) are expressed early in postnatal development, while KLF repressors (Klf9, Klf13) emerge later, functioning as a transcriptional switch.
This switch regulates genes involved in cytoskeletal functions, such as Tubb2b and Dpysl3.
Redundancy among KLF paralogs may buffer the effects of this switch, allowing for a more nuanced regulation of neuronal maturation.
Competition between KLF activators and repressors could be linked to the transition from axon growth to synaptic refinement in developing neurons.

Simplified

A critical phase of mammalian brain development takes place after birth. Neurons of the mouse neocortex undergo dramatic changes in their morphology, physiology, and synaptic connections during the first postnatal month, while properties of immature neurons, such as the capacity for robust axon outgrowth, are lost. The genetic and epigenetic programs controlling prenatal development are well studied, but our understanding of the transcriptional mechanisms that regulate postnatal neuronal maturation is comparatively lacking. By integrating chromatin accessibility and gene expression data from two subtypes of neocortical pyramidal neurons in the neonatal and maturing brain, we predicted a role for the Krüppel-like factor (KLF) family of transcription factors in the developmental regulation of neonatally expressed genes. Using a multiplexed CRISPR interference (CRISPRi) knockdown strategy, we found that a shift in expression from KLF activators (Klf6, Klf7) to repressors (Klf9, Klf13) during early postnatal development functions as a transcriptional 'switch' to first activate, then repress a set of shared targets with cytoskeletal functions including Tubb2b and Dpysl3. We demonstrate that this switch is buffered by redundancy between KLF paralogs, which our multiplexed CRISPRi strategy is equipped to overcome and study. Our results indicate that competition between activators and repressors within the KLF family regulates a conserved component of the postnatal maturation program that may underlie the loss of intrinsic axon growth in maturing neurons. This could facilitate the transition from axon growth to synaptic refinement required to stabilize mature circuits.

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Using CRISPRi to reveal a gene activity switch between KLF activators and repressors in the developing thinking areas of the brain

Abstract

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