Zfp462, also known as ZFPIP, is a vertebrate-specific zinc finger protein with nearly 2500 amino acids and 23 putative C2H2-type zinc finger domains. It is essential for embryonic development, involved in maintaining chromatin structure, and plays a role in cell pluripotency and neuronal fate determination. It may be associated with pathways related to neural development and cell division [1,3,5,6,7]. Genetic models, especially mouse models, are valuable for studying Zfp462 functions.

Zfp462 knockout (KO) mouse models have shown significant phenotypes. Zfp462 KO mice exhibit prenatal lethality, while heterozygous (Zfp462+/-) KO mice show developmental delay, low body weight, and brain weight. Behaviorally, Zfp462+/- mice display anxiety-like behaviors with excessive self-grooming, similar to Hoxb8 KO mice. The mRNA levels of Pbx1 and Hoxb8 decrease in Zfp462+/- mice brains, potentially causing these behaviors. Imipramine can rescue these abnormal behaviors [2]. In addition, Zfp462 deficiency promotes Pbx1 protein degradation through ubiquitination, down-regulates the Akt-GSK3β-CREB pathway and hippocampal neurogenesis, leading to anxiety-like behavior [4]. In mouse embryonic stem cells, loss of Zfp462 increases chromatin accessibility at target sites and causes ectopic expression of meso-endodermal genes, as Zfp462 normally targets the G9A/GLP complex to silence these genes for proper neural lineage specification [1].

In summary, Zfp462 is crucial for embryonic development, especially in neural lineage specification and maintaining normal brain-related behaviors. The Zfp462 KO mouse models have been instrumental in revealing its role in neurodevelopmental-related disease conditions such as anxiety-like behaviors, providing insights into potential therapeutic targets for such disorders [1,2,4].

References:

1. Yelagandula, Ramesh, Stecher, Karin, Novatchkova, Maria, Brennecke, Julius, Bell, Oliver. 2023. ZFP462 safeguards neural lineage specification by targeting G9A/GLP-mediated heterochromatin to silence enhancers. In Nature cell biology, 25, 42-55. doi:10.1038/s41556-022-01051-2. https://pubmed.ncbi.nlm.nih.gov/36604593/

2. Wang, B, Zheng, Y, Shi, H, Sun, M, Xu, X. 2016. Zfp462 deficiency causes anxiety-like behaviors with excessive self-grooming in mice. In Genes, brain, and behavior, 16, 296-307. doi:10.1111/gbb.12339. https://pubmed.ncbi.nlm.nih.gov/27621227/

3. Massé, Julie, Piquet-Pellorce, Claire, Viet, Justine, Pellerin, Isabelle, Deschamps, Stéphane. 2011. ZFPIP/Zfp462 is involved in P19 cell pluripotency and in their neuronal fate. In Experimental cell research, 317, 1922-34. doi:10.1016/j.yexcr.2011.04.015. https://pubmed.ncbi.nlm.nih.gov/21570965/

4. Wang, Bin, Zhu, Yichen, Wei, Bin, Zheng, Yufang, Sun, Miao. 2023. miR-377-3p Regulates Hippocampal Neurogenesis via the Zfp462-Pbx1 Pathway and Mediates Anxiety-Like Behaviors in Prenatal Hypoxic Offspring. In Molecular neurobiology, 61, 1920-1935. doi:10.1007/s12035-023-03683-3. https://pubmed.ncbi.nlm.nih.gov/37817032/

5. Chang, Yuh-Shin, Stoykova, Anastassia, Chowdhury, Kamal, Gruss, Peter. 2006. Graded expression of Zfp462 in the embryonic mouse cerebral cortex. In Gene expression patterns : GEP, 7, 405-12. doi:. https://pubmed.ncbi.nlm.nih.gov/17207666/

6. Laurent, Audrey, Masse, Julie, Omilli, Francis, Chartrain, Isabelle, Pellerin, Isabelle. 2008. ZFPIP/Zfp462 is maternally required for proper early Xenopus laevis development. In Developmental biology, 327, 169-76. doi:10.1016/j.ydbio.2008.12.005. https://pubmed.ncbi.nlm.nih.gov/19111535/

7. Massé, Julie, Laurent, Audrey, Nicol, Barbara, Pellerin, Isabelle, Deschamps, Stéphane. 2010. Involvement of ZFPIP/Zfp462 in chromatin integrity and survival of P19 pluripotent cells. In Experimental cell research, 316, 1190-201. doi:10.1016/j.yexcr.2010.02.024. https://pubmed.ncbi.nlm.nih.gov/20219459/