Abnormal Behaviors and Developmental Disorder of Hippocampus in Zinc Finger Protein 521 (ZFP521) Mutant Mice

Abstract

Zinc finger protein 521 (ZFP521) regulates a number of cellular processes in a wide range of tissues, such as osteoblast formation and adipose commitment and differentiation. In the field of neurobiology, it is reported to be an essential factor for transition of epiblast stem cells into neural progenitors in vitro. However, the role of ZFP521 in the brain in vivo still remains elusive. To elucidate the role of ZFP521 in the mouse brain, we generated mice lacking exon 4 of the ZFP521 gene. The birth ratio of our ZFP521 Δ/Δ mice was consistent with Mendel's laws. Although ZFP521 Δ/Δ pups had no apparent defect in the body and were indistinguishable from ZFP521+/+ and ZFP521 +/Δ littermates at the time of birth, ZFP521 Δ/Δ mice displayed significant weight reduction as they grew, and most of them died before 10 weeks of age. They displayed abnormal behavior, such as hyper-locomotion, lower anxiety and impaired learning, which correspond to the symptoms of schizophrenia. The border of the granular cell layer of the dentate gyrus in the hippocampus of the mice was indistinct and granular neurons were reduced in number. Furthermore, Sox1-positive neural progenitor cells in the dentate gyrus and cerebellum were significantly reduced in number. Taken together, these findings indicate that ZFP521 directly or indirectly affects the formation of the neuronal cell layers of the dentate gyrus in the hippocampus, and thus ZFP521 Δ/Δ mice displayed schizophrenia-relevant symptoms. ZFP521 Δ/Δ mice may be a useful research tool as an animal model of schizophrenia.

Conversion of Human Fibroblasts to Stably Self-Renewing Neural Stem Cells with a Single Zinc-Finger Transcription Factor

“…The importance of Zfp521 for neural development is demonstrated by the finding that NSCs/neuroectoderm cells cannot be generated from ESCs/epiblast when Zfp521 is abrogated ( Kamiya et al., 2011 ). In addition, although homozygous Zfp521 -deficient embryos apparently develop normally and are phenotypically indistinguishable from normal littermates at the time of birth, they exhibit behavioral abnormalities, lose weight over time, and are unable to survive for more than 10 weeks post-partum ( Ohkubo et al., 2014 ) indicating the indispensable roles for Zfp521 in post-natal neurogenesis and development. Zfp521 exhibits a conserved amino acid and protein domain composition across diverse animal species (>90% identity), which suggests indispensable and universal roles for Zfp521 in organismal development ( Shen et al., 2011 ).…”

Zinc Finger Proteins in Neuro-Related Diseases Progression

“…In addition, ZFP521 is co-located with P300 at the neuroectodermal locus, which requires ZFP521 to facilitate early nervous system differentiation ( Lobo et al, 2008 ; Kamiya et al, 2011 ). The lack of ZFP521 results in a reduced number of granular neurons and an indistinct border of the granular cell layer of the dentate gyrus of hippocampus ( Figure 4A ; Ohkubo et al, 2014 ). Studies have shown that decreases in neural stem cell proliferation and adult hippocampal neurogenesis in the dentate gyrus were associated with schizophrenia ( Reif et al, 2006 ; Balu and Lucki, 2009 ).…”

Zinc Finger Protein 521 Regulates Early Hematopoiesis through Cell-Extrinsic Mechanisms in the Bone Marrow Microenvironment

“…Elevated stress-related hormones, such as the glucocorticoid corticosterone, reduce the frequency of early lymphocyte progenitor populations (49-51), similar to the phenotypes seen in Zfp521 Ϫ/Ϫ mice. Furthermore, Zfp521 Ϫ/Ϫ mice are significantly runted and display abnormal behavior, which may increase the levels of stress hormones (52). However, serum levels of corticosterone were similar between 3-week-old Zfp521 Ϫ/Ϫ mice and Ctrl littermates (Fig.…”