Abstract
Dendritic spine morphology and dendritic arborization are key determinants of neuronal connectivity and play critical roles in learning, memory and behavior function. Recently, defects of ZBTB20, a BTB and zinc finger domain containing transcriptional repressor, have been implicated in a wide range of neurodevelopmental disorders, including intellectual disability and autism. Here we show distinct effects of expression of two major isoforms, long and short, of ZBTB20, and its neurodevelopmental disorder-linked variants, on dendritic architecture of cultured rat cortical pyramidal neurons. The N-terminal of ZBTB20 showed a role in regulating dendritic spine morphology. Two ZBTB20 single nucleotide variants, located at the N-terminal and central regions of the protein and potentially conferring autism risk, altered dendritic spine morphology. In contrast, a single nucleotide variant identified in patients with intellectual disability and located at the C-terminus of ZBTB20 affected dendritic arborization and dendritic length but had no effect on dendritic spine morphology. Furthermore, truncation of the extreme C-terminus of ZBTB20 caused spine and dendritic morphological changes that were similar but distinct from those caused by the C-terminal variant. Taken together, our study suggests ZBTB20’s role in dendritic and synaptic structure and provide possible mechanisms of its effect in neurodevelopmental disorders.
Highlights
Dendritic branches and spines are key regulators of neuronal function and essential for the formation and plasticity of neuronal circuits [1, 2]
Many of the few identified genes associated with neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and intellectual disability (ID) have been found to affect both structures’ number and morphology
Members of the BTB/poxvirus and zinc finger (POZ)-ZF family of transcription factors, in particular, have been shown to regulate dendritic morphology [23, 24]; we sought to examine the effect of human ZBTB20 expression on synaptic and dendritic structure
Summary
Dendritic branches and spines are key regulators of neuronal function and essential for the formation and plasticity of neuronal circuits [1, 2]. Many of the few identified genes associated with neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and intellectual disability (ID) have been found to affect both structures’ number and morphology. NDD-associated ZBTB20 gene variants affect dendritic and synaptic structure. Alliance for Research on Schizophrenia and Depression; https://www.bbrfoundation.org/) and the National Institute of Mental Health (https:// www.nimh.nih.gov/index.shtml) (R01MH10718204) to P.P., and the National Institutes of Health (https://www.nih.gov/) (1F31MH085362) to K.A.J. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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