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

Abstract

Neurodevelopmental disorders (NDDs) are multifaceted pathologic conditions manifested with intellectual disability, autistic features, psychiatric problems, motor dysfunction, and/or genetic/chromosomal abnormalities. They are associated with skewed neurogenesis and brain development, in part through dysfunction of the neural stem cells (NSCs) where abnormal transcriptional regulation on key genes play significant roles. Recent accumulated evidence highlights C 2 H 2-type zinc finger proteins (C 2 H 2-ZNFs), the largest transcription factor family in humans, as important targets for the pathologic processes associated with NDDs. In this review, we identified their significant accumulation (74 C 2 H 2-ZNFs: ∼10% of all human member proteins) in brain physiology and pathology. Specifically, we discuss their physiologic contribution to brain development, particularly focusing on their actions in NSCs. We then explain their pathologic implications in various forms of NDDs, such as morphological brain abnormalities, intellectual disabilities, and psychiatric disorders. We found an important tendency that poly-ZNFs and KRAB-ZNFs tend to be involved in the diseases that compromise gross brain structure and human-specific higher-order functions, respectively. This may be consistent with their characteristic appearance in the course of species evolution and corresponding contribution to these brain activities.

Proximity labeling identifies a repertoire of site-specific R-loop modulators

“…3 ). Zinc finger proteins are a large family of proteins with important roles in development 72 . We speculate that the dual function of zinc finger and homeodomain proteins in transcription activation and repression may be, in part, attributed to their distinct mechanisms at R-loops and to the differential effects R-loops can have in gene regulation.…”

ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export

“…Albeit the function of most ZNFs/ZFPs is still poorly understood, a group of proteins of this large family has been associated with the functionality of the nervous system (Al‐Naama et al , 2020 ). Hence, the Zic family of ZNPs is involved in the differentiation of neuronal progenitors in the medial forebrain and the cerebellum, whereas the Ikaros family has a similar function in the striatal medium spiny neurons (Inoue et al , 2008 ; Alsio et al , 2013 ).…”

Cell type diversity in a developing octopus brain

“…This pivotal study highlights the expansion of gene families such as protocadherins (PCDH), G-protein coupled receptors (GPCR) and Zinc-finger transcription factors (ZnF) in Octopus bimaculoides 12 . These gene families have known roles in brain development and neural wiring in complex-brain species [13][14][15] . Whether these peculiar expansions have contributed to cell type diversity in octopus is unknown.…”