Severe Fanconi Anemia phenotypes in Fancd2 depletion mice

Qiao Yang; Hui Xie; Yixinhe Zhong; Dongbo Li; Xianfu Ke; Huazhong Ying; Bing Yu; Tingting Zhang

doi:10.1016/j.bbrc.2019.04.201

Severe Fanconi Anemia phenotypes in Fancd2 depletion mice

Biochem Biophys Res Commun. 2019 Jun 30;514(3):713-719. doi: 10.1016/j.bbrc.2019.04.201. Epub 2019 May 9.

Authors

Qiao Yang¹, Hui Xie², Yixinhe Zhong¹, Dongbo Li¹, Xianfu Ke², Huazhong Ying², Bing Yu³, Tingting Zhang⁴

Affiliations

¹ Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China; Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, China.
² Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, China.
³ Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
⁴ Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, China. Electronic address: tingting.zhang@zjams.com.cn.

PMID: 31078270
DOI: 10.1016/j.bbrc.2019.04.201

Abstract

Fanconi anemia (FA) is a genetic disorder characterized by congenital malfunction, bone marrow failure and hypersensitivity to DNA damage. FANCD2 protein play the central role in FA pathway. To study the in vivo role of FANCD2, we generated and characterized a new Fancd2 knockout mouse strain with 7bp deletion in Fancd2 gene 5' terminus using Crispr-Cas9 in congenic C57BL/6J background. This Fancd2^-/- mice displayed similar but overall more severe manifestation than the previous ES cell targeted Fancd2 model. These features include increased embryonic and postnatal lethality rate, higher incidence of microphthalmia, and more severe hypogonadism. The anemia we observed in this Fancd2^-/- mice has not been described in other FA models. Further study indicated that the hematopoiesis deficiency was associated with increased apoptotic cell death, G2/M phase arrest and hypersensitivity to MMC and IR damage of Fancd2^-/- bone marrow progenitor cells. Collectively, the resulting Fancd2^-/- mice with higher resemblance of FA patient symptoms, will be useful in understand the parthenogenesis of pancytopenia and bone marrow failure in FA.

Keywords: Crispr-Cas9; FANCD2; Fanconi anemia; Mouse model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anemia / pathology
Animals
Base Sequence
Bone Marrow Cells / drug effects
Bone Marrow Cells / metabolism
Bone Marrow Cells / radiation effects
CRISPR-Associated Protein 9 / metabolism
CRISPR-Cas Systems / genetics
Fanconi Anemia / pathology*
Fanconi Anemia Complementation Group D2 Protein / deficiency*
Fanconi Anemia Complementation Group D2 Protein / metabolism
Female
Hematopoiesis / drug effects
Hematopoiesis / radiation effects
Mice, Inbred C57BL
Mice, Knockout
Mitomycin / pharmacology
Phenotype
Radiation, Ionizing
Stem Cells / drug effects
Stem Cells / metabolism
Stem Cells / radiation effects

Substances

Fanconi Anemia Complementation Group D2 Protein
Mitomycin
CRISPR-Associated Protein 9