Multiplexed CRISPRi reveals a transcriptional switch between KLF activators and repressors in the maturing neocortex
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…
During the first month postnatal in the mouse neocortex, neurons undergo significant changes in their morphology, physiology, and synaptic connections. The genes and epigenetic factors involved in prenatal development are well-documented, but the transcriptional mechanisms governing postnatal neuronal maturation are less understood.
By analyzing chromatin accessibility and gene expression data from two types of neocortical pyramidal neurons, researchers identified a potential role for the Krüppel-like factor (KLF) family of transcription factors in this developmental process.
Using a multiplexed CRISPR interference (CRISPRi) knockdown strategy, the researchers discovered that a shift from KLF activators (Klf6, Klf7) to repressors (Klf9, Klf13) during early postnatal development acts as a "transcriptional switch." This switch first activates, and then represses, a set of shared target genes with cytoskeletal functions such as Tubb2b and Dpysl3. The multiplexed CRISPRi strategy overcomes redundancy between KLF paralogs, enabling the examination of this critical switch.
The findings suggest that competition between activators and repressors within the KLF family governs a conserved component of the postnatal maturation program, potentially explaining the loss of axon growth in maturing neurons. This transition from axon growth to synaptic refinement is essential for stabilizing mature circuits within the developing brain.
Written by urgent.news from eLife's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
