Knockout of the fcsk gene in zebrafish causes neurodevelopmental defects

被引:0
|
作者
Liu, Zhen-Xing [1 ,2 ]
Zou, Ting-Ting [1 ,2 ]
Liu, Hui-Hui [1 ,2 ]
Jia, Hai-Bo [1 ,2 ]
Zhang, Xian-Qin [1 ,2 ]
机构
[1] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Key Lab Mol Biophys, Minist Educ, Wuhan 430074, Hubei, Peoples R China
[2] Huazhong Univ Sci & Technol, Ctr Human Genome Res, Wuhan 430074, Hubei, Peoples R China
基金
中国国家自然科学基金; 国家重点研发计划;
关键词
Congenital disorders of glycosylation; fcsk; Zebrafish; Behavior; RNA sequencing; MUTATIONS; PROTEIN; GLYCOSYLATION; FUCOSYLATION; DISORDER; FUS;
D O I
10.24272/j.issn.2095-8137.2024.229
中图分类号
Q95 [动物学];
学科分类号
071002 ;
摘要
Congenital disorders of glycosylation (CDG) are a cluster of monogenic disorders resulting from defects in glycosylation. FCSK encodes fucokinase, an enzyme that catalyzes the phosphorylation of L-fucose to generate fucose-1-phosphate, an important step in fucosylation. Mutations in FCSK lead to CDG with an autosomal recessive inheritance pattern, primarily manifesting as developmental delay, hypotonia, and brain abnormalities. However, no fcsk mutant animal models have yet been established. This study constructed the first fcsk knockout (fcsk-/-) zebrafish model using CRISPR/Cas9 technology. Notably, fcsk-/- zebrafish exhibited impaired growth, characterized by delayed epiboly and DNA accumulation during early embryonic development, as well as brain atrophy in adulthood. Larval-stage fcsk-/- zebrafish displayed locomotor deficits and increased susceptibility to pentylenetetrazole-induced seizures. In adulthood, fcsk-/- zebrafish showed neurodevelopmental abnormalities, including increased anxiety, decreased aggression, reduced social preference, and impaired memory. Additionally, total protein fucosylation was markedly reduced in fcsk-/- zebrafish, accompanied by decreased expression of pofut2, which encodes protein Ofucosyltransferase 2, an enzyme involved in the fucosylation salvage pathway. Apoptotic activity was elevated in the midbrain-hindbrain boundary (MHB) of fcsk-/- zebrafish. Supplementation with GDP-L-fucose or the human FCSK gene restored developmental defects and total protein fucosylation in fcsk-/- zebrafish. RNA sequencing revealed dysregulated gene expression associated with glycosylation, apoptosis, and neurodegenerative diseases. These findings suggest that fcsk-/- zebrafish exhibit neurodevelopmental disorders, providing the first fcsk gene knockout animal model and offering a platform for investigating the molecular underpinnings of the disease and facilitating drug screening efforts.
引用
收藏
页码:313 / 324
页数:12
相关论文
共 50 条
  • [31] Knockout of frataxin gene causes embryo lethality in Arabidopsis
    Murgia, I.
    Vazzola, V.
    Losa, A.
    Soave, C.
    AMERICAN JOURNAL OF HEMATOLOGY, 2007, 82 (06) : 516 - 517
  • [32] CRISPR-Cas9-induced gene knockout in zebrafish
    Medishetti, Raghavender
    Balamurugan, Keerthana
    Yadavalli, Krishnaveni
    Rani, Rita
    Sevilimedu, Aarti
    Challa, Anil Kumar
    Parsa, Kishore
    Chatti, Kiranam
    STAR PROTOCOLS, 2022, 3 (04):
  • [33] A nonsense mutation in the gene encoding a zebrafish myosin VI isoform causes defects in hair-cell mechanotransduction
    Kappler, JA
    Starr, CJ
    Chan, DK
    Kollmar, R
    Hudspeth, AJ
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (35) : 13056 - 13061
  • [34] Characterizing zebrafish lens abnormalities following CRISPR gene knockout
    Posner, Mason
    Butterbaugh, Alexis
    Kaye, Taylor
    Hussen, Adil
    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2021, 62 (08)
  • [35] DISC1 causes associative memory and neurodevelopmental defects in fruit flies
    Furukubo-Tokunaga, K.
    Kurita, K.
    Honjo, K.
    Pandey, H.
    Ando, T.
    Takayama, K.
    Arai, Y.
    Mochizuki, H.
    Ando, M.
    Kamiya, A.
    Sawa, A.
    MOLECULAR PSYCHIATRY, 2016, 21 (09) : 1232 - 1243
  • [36] Carboxyl graphene oxide nanoparticles induce neurodevelopmental defects and locomotor disorders in zebrafish larvae
    Cao, Zigang
    Su, Meile
    Wang, Honglei
    Zhou, Liqun
    Meng, Zhen
    Xiong, Guanghua
    Liao, Xinjun
    Lu, Huiqiang
    CHEMOSPHERE, 2021, 270
  • [37] DISC1 causes associative memory and neurodevelopmental defects in fruit flies
    K Furukubo-Tokunaga
    K Kurita
    K Honjo
    H Pandey
    T Ando
    K Takayama
    Y Arai
    H Mochizuki
    M Ando
    A Kamiya
    A Sawa
    Molecular Psychiatry, 2016, 21 : 1232 - 1243
  • [38] Deletion of Pr72 causes cardiac developmental defects in Zebrafish
    Song, Guibo
    Han, Mingjun
    Li, Zuhua
    Gan, Xuedong
    Chen, Xiaowen
    Yang, Jie
    Dong, Sufang
    Yan, Ming
    Wan, Jun
    Wang, Yanggan
    Huang, Zhuliang
    Yin, Zhan
    Zheng, Fang
    PLOS ONE, 2018, 13 (11):
  • [39] Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish
    Lin, Sheng-Jia
    Vona, Barbara
    Barbalho, Patricia G.
    Kaiyrzhanov, Rauan
    Maroofian, Reza
    Petree, Cassidy
    Severino, Mariasavina
    Stanley, Valentina
    Varshney, Pratishtha
    Bahena, Paulina
    Alzahrani, Fatema
    Alhashem, Amal
    Pagnamenta, Alistair T.
    Aubertin, Gudrun
    Estrada-Veras, Juvianee I.
    Hernandez, Hector Adrian Diaz
    Mazaheri, Neda
    Oza, Andrea
    Thies, Jenny
    Renaud, Deborah L.
    Dugad, Sanmati
    McEvoy, Jennifer
    Sultan, Tipu
    Pais, Lynn S.
    Tabarki, Brahim
    Villalobos-Ramirez, Daniel
    Rad, Aboulfazl
    Galehdari, Hamid
    Ashrafzadeh, Farah
    Sahebzamani, Afsaneh
    Saeidi, Kolsoum
    Torti, Erin
    Elloumi, Houda Z.
    Mora, Sara
    Palculict, Timothy B.
    Yang, Hui
    Wren, Jonathan D.
    Fowler, Ben
    Joshi, Manali
    Behra, Martine
    Burgess, Shawn M.
    Nath, Swapan K.
    Hanna, Michael G.
    Kenna, Margaret
    Merritt, J. Lawrence, II
    Houlden, Henry
    Karimiani, Ehsan Ghayoor
    Zaki, Maha S.
    Haaf, Thomas
    Alkuraya, Fowzan S.
    GENETICS IN MEDICINE, 2021, 23 (10) : 1933 - 1943
  • [40] Betaglycan Knock-Down Causes Embryonic Angiogenesis Defects in Zebrafish
    Kamaid, Andres
    Molina-Villa, Tonatiuh
    Mendoza, Valentin
    Pujades, Cristina
    Maldonado, Ernesto
    Belmonte, Juan Carlos Ispizua
    Lopez-Casillas, Fernando
    GENESIS, 2015, 53 (09) : 583 - 603