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 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.

Keywords: KRAB domain; brain development; mutation; neural stem cells; structural abnormality; transcriptional regulation.

Figure 1

Protein structure of the representative human C₂H₂-ZNFs. Protein structure of ZIC1 (Poly-ZF), ZBTB7C (POZ/BTB-ZNF), ZNF74, ZNF18 (KRAB-ZNFs), and ZSCAN10 (SCAN-ZNF) are shown as representatives of respective subtypes. Some C₂H₂-ZNFs have multiples of the same or different domains as indicated in ZNF18. Location and length of the respective domains are based on the data from the UniProt (https://www.uniprot.org/) and/or the National Center of Biotechnology Information (NCBI) Conserved Domain (https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi). Numbers in brackets indicate amino acid numbers. ZF, C₂H₂-type zinc finger; KRAB, KRAB domain; POZ/BTB, POZ/BTB domain; SCAN, SCAN domain.