Deficiency of smarcal1 causes cell cycle arrest and developmental abnormalities in zebrafish

Mutations in SMARCAL1 cause Schimke Immuno-Osseous Dysplasia (SIOD), an autosomal recessive multisystem developmental disease characterized by growth retardation, T-cell deficiency, bone marrow failure, anemia and renal failure. SMARCAL1 encodes an ATP-driven annealing helicase. However, the biologi...

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Bibliographic Details
Published in:Developmental biology 2010-03, Vol.339 (1), p.89-100
Main Authors: Huang, Cheng, Gu, Shanye, Yu, Pengchun, Yu, Fudong, Feng, Chun, Gao, Ning, Du, Jiulin
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Base Sequence
Blotting, Western
Cell Cycle
Chromatin remodeling
Danio rerio
Development
DNA Helicases - genetics
DNA Helicases - physiology
DNA Primers
Electrophoretic Mobility Shift Assay
Gene Knockdown Techniques
In Situ Hybridization
Mutation
Reverse Transcriptase Polymerase Chain Reaction
Schimke Immuno-Osseous Dysplasia
smarcal1
Zebrafish - embryology
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Summary:Mutations in SMARCAL1 cause Schimke Immuno-Osseous Dysplasia (SIOD), an autosomal recessive multisystem developmental disease characterized by growth retardation, T-cell deficiency, bone marrow failure, anemia and renal failure. SMARCAL1 encodes an ATP-driven annealing helicase. However, the biological function of SMARCAL1 and the molecular basis of SIOD remain largely unclear. In this work, we cloned the zebrafish homologue of the human SMARCAL1 gene and found that smarcal1 regulated cell cycle progression. Morpholino knockdown of smarcal1 in zebrafish recapitulated developmental abnormalities in SIOD patients, including growth retardation, craniofacial abnormality, and haematopoietic and vascular defects. Lack of smarcal1 caused G0/G1 cell cycle arrest and induced cell apoptosis. Furthermore, using Electrophoretic Mobility Shift Assay and reporter assay, we found that SMARCAL1 was transcriptionally inhibited by E2F6, an important cell cycle regulator. Over-expression of E2F6 in zebrafish embryos reduced the expression of smarcal1 mRNA and induced developmental defects similar to those in smarcal1 morphants. These results suggest that SIOD may be caused by defects in cell cycle regulation. Our study provides a model of SIOD and reveals its cellular and molecular bases.
ISSN:0012-1606
1095-564X
DOI:10.1016/j.ydbio.2009.12.018