Zbtb16 regulates social cognitive behaviors and neocortical development

Abstract

Zinc finger and BTB domain containing 16 (ZBTB16) play the roles in the neural progenitor cell proliferation and neuronal differentiation during development, however, how the function of ZBTB16 is involved in brain function and behaviors unknown. Here we show the deletion of Zbtb16 in mice leads to social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we conducted histological analyses and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia, as well as developmental defects in oligodendrocytes and neocortical myelination in the prefrontal cortex (PFC) of Zbtb16 KO mice. Using genomics approaches, we identified the Zbtb16 transcriptome that includes genes involved in neocortical maturation such as neurogenesis and myelination, and both autism spectrum disorder (ASD) and schizophrenia (SCZ) pathobiology. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ, respectively. Our study provides insight into the novel roles of ZBTB16 in behaviors and neocortical development related to the disorders.

Zinc Finger Proteins in Neuro-Related Diseases Progression

“… Kruszka et al (2019) describe a multiple congenital anomaly syndrome associated with haploinsufficiency of zinc finger protein 462 in which most patients have developmental delay (79%) and a minority have ASD (33%). Zinc finger and BTB domain containing 16 (ZBTB16) from C2H2 type subfamily plays the roles in the neural progenitor cell proliferation and neuronal differentiation during development, and associates with ASD and schizophrenia pathobiology ( Usui et al, 2021 ). Another zinc finger protein associated with neural development is BAZ2B, which from PHD-type can interact with ISWI (imitation switch) and may play a role in transcriptional regulation ( Jones et al, 2000 ; Oppikofer et al, 2017 ).…”

Early Life Stress Alters Gene Expression and Cytoarchitecture in the Prefrontal Cortex Leading to Social Impairment and Increased Anxiety

“…Zbtb16 KO mice displayed ASD-like behaviors such as social impairment and increased repetitive behaviors as well as cognitive impairment ( Usui et al, 2021a ). However, Zbtb16 KO mice showed antianxiety-like (risk-taking) behaviors ( Usui et al, 2021a ). Per2 is known as a clock gene of Period family and controls circadian rhythm under the CLOCK/ARNTL regulation ( Takahashi, 2017 ; Rijo-Ferreira and Takahashi, 2019 ).…”

Table1.XLSX

“…ZBTB16 is associated with ASD (Bacchelli et al, 2019) and skeletal defects, genital hypoplasia, and mental retardation (SGYMR) (Wieczorek et al, 2002;Fischer et al, 2008). Zbtb16 KO mice displayed ASD-like behaviors such as social impairment and increased repetitive behaviors as well as cognitive impairment (Usui et al, 2021a). However, Zbtb16 KO mice showed antianxiety-like (risk-taking) behaviors (Usui et al, 2021a).…”

“…Marble-burying test was performed as described previously (Usui et al, 2021a). Mice were placed in the corner of a novel home cage evenly placed eighteen marbles and allowed to freely explore for 20 min.…”

“…Immunohistochemistry was performed as described previously (Usui et al, 2021a). The mouse brain was fixed with 4% PFA in PBS overnight at 4 °C, cryoprotected in 30% sucrose in PBS overnight at 4 °C, and then embedded in Tissue-Tek O.C.T.…”