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

Njoud Al-Naama,Tomoshige Kino,Rafah Mackeh

doi:10.3389/fneur.2020.00032

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 C2H2-type zinc finger proteins (C2H2-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 C2H2-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.

Highlights

Neurodevelopmental disorders (NDDs) are multifaceted pathologic conditions caused by skewed development of the central nervous system (CNS) and subsequent morphological and/or functional abnormalities [1]
The pathologic mechanisms developing NDDs emerge during the early stage of brain development organized in utero and in childhood, and this is largely due to significant involvement of genome deficits in various key genes required for normal brain development [2]
ZNF804A expresses a poly-ZNF harboring just one zinc fingers (ZFs), and its reduced expression is likely important for the development of schizophrenia in part by changing the expression of the genes involved in neural cell adhesion, neurite outgrowth, and synapse formation [155]

Summary

Introduction

Neurodevelopmental disorders (NDDs) are multifaceted pathologic conditions caused by skewed development of the central nervous system (CNS) and subsequent morphological and/or functional abnormalities [1]. POGZ, a unique poly-ZNF harboring the transposase domain at its C-terminus in addition to nine ZFs [145], is highly expressed in the human fetal brain and is involved in mitosis and regulation of neural proliferation [145].

Results

Conclusion