Neurodevelopmental disorder-associated ZBTB20 gene variants affect dendritic and synaptic structure

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.

SUMOylation controls the neurodevelopmental function of the transcription factor Zbtb20

“…In the mouse brain, Zbtb20 expression is required for cell subtype specification in hippocampus neurons and for neuronal morphogenesis (Jones et al, 2018; Nielsen, Blom, Noraberg, & Jensen, 2010; Rosenthal et al, 2012). Consequently, we decided to assess the role of Zbtb20 and its SUMOylation in neuronal morphogenesis in vitro.…”

“…Several point mutations in Zbtb20, as well as several truncations, have been linked to various neurological disorders, including intellectual disability, autism, and Primrose syndrome (Cordeddu et al, 2014;Jones et al, 2018;Rasmussen, Nielsen, & Lourenco, 2014).…”

“…As outlined earlier, the precise molecular mechanism by which SUMOylation alters Zbtb20 function remains to be determined. Several point mutations in Zbtb20 , as well as several truncations, have been linked to various neurological disorders, including intellectual disability, autism, and Primrose syndrome (Cordeddu et al, 2014; Jones et al, 2018; Rasmussen, Nielsen, & Lourenco, 2014). In many cases, point mutations in the zinc‐finger region of Zbtb20 were described, which directly affect DNA‐binding and are most likely unrelated to the SUMOylation status of Zbtb20 (Cordeddu et al, 2014).…”

“…In many cases, point mutations in the zinc‐finger region of Zbtb20 were described, which directly affect DNA‐binding and are most likely unrelated to the SUMOylation status of Zbtb20 (Cordeddu et al, 2014). A point mutation located in the central region of Zbtb20 and more proximal to the SUMO acceptors lysines was shown to be linked to autism‐spectrum disorder and to affect spine morphology, but the SUMOylation status of Zbtb20 was not studied in this context (Jones et al, 2018).…”

C2H2-Type Zinc Finger Proteins in Brain Development, Neurodevelopmental, and Other Neuropsychiatric Disorders: Systematic Literature-Based Analysis

“…ZNF18 is a KRAB-ZNF with one SCAN domain, and is upregulated upon depolarization in mouse neuronal cells, suggesting its potential activity-dependent roles (85). The ZBTB20 gene is also involved in the development of ASDs in addition to other types of NDDs including 3q13.31 microdeletion and microduplication syndrome, Primrose syndrome and ID (72,(137)(138)(139). ZBTB20 is a BTB/POZ-ZNF mainly expressed in the developing forebrain neocortex and is involved in cortical neurogenesis, hippocampal neuronal differentiation and connectivity, and promotes astrocytogenesis (140).…”