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Review
. 2019 Jun 13;17:954-962.
doi: 10.1016/j.csbj.2019.06.006. eCollection 2019.

The Progress of CRISPR/Cas9-Mediated Gene Editing in Generating Mouse/Zebrafish Models of Human Skeletal Diseases

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Free PMC article
Review

The Progress of CRISPR/Cas9-Mediated Gene Editing in Generating Mouse/Zebrafish Models of Human Skeletal Diseases

Nan Wu et al. Comput Struct Biotechnol J. .
Free PMC article

Abstract

Genetic factors play a substantial role in the etiology of skeletal diseases, which involve 1) defects in skeletal development, including intramembranous ossification and endochondral ossification; 2) defects in skeletal metabolism, including late bone growth and bone remodeling; 3) defects in early developmental processes related to skeletal diseases, such as neural crest cell (NCC) and cilia functions; 4) disturbance of the cellular signaling pathways which potentially affect bone growth. Efficient and high-throughput genetic methods have enabled the exploration and verification of disease-causing genes and variants. Animal models including mouse and zebrafish have been extensively used in functional mechanism studies of causal genes and variants. The conventional approaches of generating mutant animal models include spontaneous mutagenesis, random integration, and targeted integration via mouse embryonic stem cells. These approaches are costly and time-consuming. Recent development and application of gene-editing tools, especially the CRISPR/Cas9 system, has significantly accelerated the process of gene-editing in diverse organisms. Here we review both mice and zebrafish models of human skeletal diseases generated by CRISPR/Cas9 system, and their contributions to deciphering the underpins of disease mechanisms.

Figures

Unlabelled Image
Fig. 1
Fig. 1
Mechanism of the CRISPR-Cas9 targeting system. 1. A sgRNA matches and binds to a 20-nt DNA sequence immediately upstream of an NGG DNA motif (Protospacer-Associated Motif, PAM). 2. The Cas9 protein is guided to the loci by the sgRNA and cuts both strands 3 bp upstream of the NGG. 3. The double-stranded DNA breaks activate the cellular DNA repair machinery, resulting in nonhomologous end joining (NHEJ) or homology-directed repair (HDR).
Fig. 2
Fig. 2
Manipulation of genes participating in various physiological processes Human genes and genotypes/mutated-alleles of corresponding skeletal diseases related animal models are shown in the main physiological processes of bone development and remodeling. CRISPR/Cas9 system contributes to the establishment of those animal models. Abbreviations: CSF, cerebrospinal fluid.

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