Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation

Abstract Although Krüppel-associated box domain-containing zinc-finger proteins (K-ZNFs) may be associated with sophisticated gene regulation in higher organisms, the physiological functions of most K-ZNFs remain unknown. The Zfp212 protein was highly conserved in mammals and abundant in the brain;...

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Autores principales:	Rin Khang, Areum Jo, Hojin Kang, Hanna Kim, Eunsang Kwag, Ji-Yeong Lee, Okjae Koo, Jinsu Park, Hark Kyun Kim, Dong-Gyu Jo, Inwoo Hwang, Jee-Yin Ahn, Yunjong Lee, Jeong-Yun Choi, Yun-Song Lee, Joo-Ho Shin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d066dbca80bf45fa93f045bb7639c08f
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spelling	oai:doaj.org-article:d066dbca80bf45fa93f045bb7639c08f2021-11-28T12:20:58ZLoss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation10.1038/s41598-021-02218-x2045-2322https://doaj.org/article/d066dbca80bf45fa93f045bb7639c08f2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02218-xhttps://doaj.org/toc/2045-2322Abstract Although Krüppel-associated box domain-containing zinc-finger proteins (K-ZNFs) may be associated with sophisticated gene regulation in higher organisms, the physiological functions of most K-ZNFs remain unknown. The Zfp212 protein was highly conserved in mammals and abundant in the brain; it was mainly expressed in the cerebellum (Cb). Zfp212 (mouse homolog of human ZNF212) knockout (Zfp212-KO) mice showed a reduction in survival rate compared to wild-type mice after 20 months of age. GABAergic Purkinje cell degeneration in the Cb and aberrant locomotion were observed in adult Zfp212-KO mice. To identify genes related to the ataxia-like phenotype of Zfp212-KO mice, 39 ataxia-associated genes in the Cb were monitored. Substantial alterations in the expression of ataxin 10, protein phosphatase 2 regulatory subunit beta, protein kinase C gamma, and phospholipase D3 (Pld3) were observed. Among them, Pld3 alone was tightly regulated by Flag-tagged ZNF212 overexpression or Zfp212 knockdown in the HT22 cell line. The Cyclic Amplification and Selection of Targets assay identified the TATTTC sequence as a recognition motif of ZNF212, and these motifs occurred in both human and mouse PLD3 gene promoters. Adeno-associated virus-mediated introduction of human ZNF212 into the Cb of 3-week-old Zfp212-KO mice prevented Purkinje cell death and motor behavioral deficits. We confirmed the reduction of Zfp212 and Pld3 in the Cb of an alcohol-induced cerebellar degeneration mouse model, suggesting that the ZNF212–PLD3 relationship is important for Purkinje cell survival.Rin KhangAreum JoHojin KangHanna KimEunsang KwagJi-Yeong LeeOkjae KooJinsu ParkHark Kyun KimDong-Gyu JoInwoo HwangJee-Yin AhnYunjong LeeJeong-Yun ChoiYun-Song LeeJoo-Ho ShinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rin Khang Areum Jo Hojin Kang Hanna Kim Eunsang Kwag Ji-Yeong Lee Okjae Koo Jinsu Park Hark Kyun Kim Dong-Gyu Jo Inwoo Hwang Jee-Yin Ahn Yunjong Lee Jeong-Yun Choi Yun-Song Lee Joo-Ho Shin Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation
description	Abstract Although Krüppel-associated box domain-containing zinc-finger proteins (K-ZNFs) may be associated with sophisticated gene regulation in higher organisms, the physiological functions of most K-ZNFs remain unknown. The Zfp212 protein was highly conserved in mammals and abundant in the brain; it was mainly expressed in the cerebellum (Cb). Zfp212 (mouse homolog of human ZNF212) knockout (Zfp212-KO) mice showed a reduction in survival rate compared to wild-type mice after 20 months of age. GABAergic Purkinje cell degeneration in the Cb and aberrant locomotion were observed in adult Zfp212-KO mice. To identify genes related to the ataxia-like phenotype of Zfp212-KO mice, 39 ataxia-associated genes in the Cb were monitored. Substantial alterations in the expression of ataxin 10, protein phosphatase 2 regulatory subunit beta, protein kinase C gamma, and phospholipase D3 (Pld3) were observed. Among them, Pld3 alone was tightly regulated by Flag-tagged ZNF212 overexpression or Zfp212 knockdown in the HT22 cell line. The Cyclic Amplification and Selection of Targets assay identified the TATTTC sequence as a recognition motif of ZNF212, and these motifs occurred in both human and mouse PLD3 gene promoters. Adeno-associated virus-mediated introduction of human ZNF212 into the Cb of 3-week-old Zfp212-KO mice prevented Purkinje cell death and motor behavioral deficits. We confirmed the reduction of Zfp212 and Pld3 in the Cb of an alcohol-induced cerebellar degeneration mouse model, suggesting that the ZNF212–PLD3 relationship is important for Purkinje cell survival.
format	article
author	Rin Khang Areum Jo Hojin Kang Hanna Kim Eunsang Kwag Ji-Yeong Lee Okjae Koo Jinsu Park Hark Kyun Kim Dong-Gyu Jo Inwoo Hwang Jee-Yin Ahn Yunjong Lee Jeong-Yun Choi Yun-Song Lee Joo-Ho Shin
author_facet	Rin Khang Areum Jo Hojin Kang Hanna Kim Eunsang Kwag Ji-Yeong Lee Okjae Koo Jinsu Park Hark Kyun Kim Dong-Gyu Jo Inwoo Hwang Jee-Yin Ahn Yunjong Lee Jeong-Yun Choi Yun-Song Lee Joo-Ho Shin
author_sort	Rin Khang
title	Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation
title_short	Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation
title_full	Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation
title_fullStr	Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation
title_full_unstemmed	Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation
title_sort	loss of zinc-finger protein 212 leads to purkinje cell death and locomotive abnormalities with phospholipase d3 downregulation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d066dbca80bf45fa93f045bb7639c08f
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Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation

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