Loss of the neuronal genome organizer and transcription factor CTCF induces neuronal death and reactive gliosis in the anterior cingulate cortex

Abstract

CCCTC‐binding factor (CTCF) is a genome organizer that regulates gene expression through transcription and chromatin structure regulation. CTCF also plays an important role during the developmental and adult stages. Cell‐specific CTCF deletion studies have shown that a reduction in CTCF expression leads to the development of distinct clinical features and cognitive disorders. Therefore, we knocked out Ctcf (CTCF cKO) in the excitatory neurons of the forebrain in a Camk2a‐Cre mouse strain to examine the role of CTCF in cell death and gliosis in the cortex. CTCF cKO mice were viable, but they demonstrated an age‐dependent increase in reactive gliosis of astrocytes and microglia in the anterior cingulate cortex (ACC) from 16 weeks of age prior to neuronal loss observed at over 20 weeks of age. Consistent with these data, qRT‐PCR analysis of the CTCF cKO ACC revealed changes in the expression of inflammation‐related genes (Hspa1a, Prokr2 and Itga8) linked to gliosis and neuronal death. Our results suggest that prolonged Ctcf gene deficiency in excitatory neurons results in neuronal cell death and gliosis, possibly through functional changes in inflammation‐related genes.

Forebrain glutamatergic neuron-specific Ctcf deletion induces reactive microgliosis and astrogliosis with neuronal loss in adult mouse hippocampus

“…Neuronal death following sequential microgliosis and astro-gliosis was also observed in the anterior cingulate cortex (ACC) of cKO mice. Indeed, our previous study on the ACC demonstrated apoptotic cell death of cortical neurons in cKO mice over 5 months of age, subsequent to age-dependent aggravation in reactive gliosis at 4 months of age ( 15 ). However, in the present study, we found that hippocampal neuronal damage and death induced by CTCF deficiency occur later than cortical neuronal death of the ACC and we assume that it might attribute to enrichment of neurogenesis-related genes in the hippocampus.…”

“…( 7 ) and Kwak et al . ( 15 ). Littermates without the Cre transgene or the floxed Ctcf gene were used as controls (CTL).…”

Conditional knock out of transcription factor CTCF in excitatory neurons induces cognitive deficiency

“…We showed that Ctcf gene deficiency leads to altered gene expression and impaired synaptic plasticity in the forebrain of adult mice [4,6]. Moreover, recently we also showed neuroinflammation with reactive gliosis in the cortex from 16 weeks of age accompanied by neuronal cell death at over 20 weeks of age in forebrain glutamatergic neuronspecific Ctcf gene KO (CTCF cKO) mice [7].…”

“…In this study, we showed that adult CTCF cKO mice exhibited signs of lack of behavioral flexibility and cognitive dysfunction in the PDr and dPAL touch screen test. These cognitive impairments are likely due to the loss of glutamatergic neurons in the cortex, particularly in the ACC, as inhibitory neurons in the striatum are relatively intact in adult CTCF cKO mice [7]. ACC is known to be involved in behavioral flexibility as well as decision making, adaptation, and anticipation in rodents [11].…”

“…Therefore, it is possible that CTCF deficiency in the ACC may lead to lack of behavior flexibility in adult CTCF cKO mouse. Although CTCF deficiency has been demonstrated to be prominent in the ACC [7], which plays a critical role in remote memory formation [12,13], pain processing [12], and other higher cognitive functions [14], other forebrain areas may also contribute to the cognitive dysfunction induced by CTCF deficiency. As we reported previously, the hippocampus plays a key role in dPAL leaning [9].…”