CTCF in parvalbumin-expressing neurons regulates motor, anxiety and social behavior and neuronal identity

Abstract

CCCTC-binding factor (CTCF) is a regulator of chromatin organization and has direct effects on gene transcription. Mutations in CTCF have been identified in individuals with neurodevelopmental conditions. There are wide range of behaviors associated with these mutations, including intellectual disabilities, changes in temperament, and autism. Previous mice-model studies have identified roles for CTCF in excitatory neurons in specific behaviors, particularly in regards to learning and memory. However, the role of CTCF in inhibitory neurons is less well defined. In the current study, specific knockout of CTCF in parvalbumin-expressing neurons, a subset of inhibitory neurons, induced a specific behavioral phenotype, including locomotor abnormalities, anxiolytic behavior, and a decrease in social behavior. The anxiolytic and social abnormalities are detected before the onset of locomotor abnormalities. Immunohistochemical analysis revealed a disbalance in parvalbumin-expressing and somatostatin-expressing cells in these mice. Single nuclei RNA sequencing identified changes in gene expression in parvalbumin-expressing neurons that are specific to inhibitory neuronal identity and function. Electrophysiology analysis revealed an enhanced inhibitory tone in the hippocampal pyramidal neurons in knockout mice. These findings indicate that CTCF in parvalbumin-expressing neurons has a significant role in the overall phenotype of CTCF-associated neurodevelopmental deficits.

An updated catalog of CTCF variants associated with neurodevelopmental disorder phenotypes

“…Based on total allele counts, 3 ′ UTR variants were the most common, identified in nearly 30,000 genomes, followed by exonic synonymous variants, intronic, and then exonic missense variants (Supplementary Figure 2B). As expected, no frameshift variants were reported, consistent with the pathogenic haploinsufficiency model of NDD resulting from loss of CTCF (Hirayama et al, 2012;Watson et al, 2014;Sams et al, 2016;Davis et al, 2022). 29% of SNPs were located within exons.…”

“…Conditional knockout of CTCF in mouse neurons at various stages of development has produced phenotypes including disorganized brain development, increased neuronal apoptosis, behavioral and learning deficits, and premature death (Hirayama et al, 2012 ; Watson et al, 2014 ; Sams et al, 2016 ; Davis et al, 2022 ). Together, these studies highlight the central role that CTCF plays in maintaining correct 3D genome structure and gene expression, which are essential for proper neurodevelopment.…”

Editorial: The commonality in converged pathways and mechanisms underpinning neurodevelopmental and psychiatric disorders

“…CTCF haploinsufficiency mice display altered DNA methylation landscape and dysregulated gene expression patterns and are predisposed to both spontaneous and induced tumor incidence (Alharbi et al, 2021 ). Conditional deletion of CTCF at various stages of development in mice can cause disorganized brain development, increased apoptosis, behavioral and learning deficits and even premature death (Hirayama et al, 2012 ; Davis et al, 2022 ). These data strongly highlight the essential role of CTCF for proper neurodevelopment.…”

Nuclear envelope, chromatin organizers, histones, and DNA: The many achilles heels exploited across cancers

“…What effects chemotherapeutic agents have on TAD organization and gene expression in vivo remains an area of active study. Moreover, it is intriguing that environmental factors, such as diet and social interaction, also impinge on CTCF function and, therefore, chromatin organization and function (Davis et al, 2022;)-an interesting finding, given that extraneous environmental factors considerably contribute to an increase in the incidence of cancers.…”