title: Deficiency of smarcal1 causes cell cycle arrest and developmental abnormalities in zebrafish.
abstract: 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.
authors.affiliation: Institute for Nutritional Sciences and Key Laboratory of Nutrition and Metabolism, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. chuang@sibs.ac.cn
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.forename: Shanye
authors.initials: S
authors.lastname: Gu
authors.forename: Pengchun
authors.initials: P
authors.lastname: Yu
authors.forename: Fudong
authors.initials: F
authors.lastname: Yu
authors.forename: Chun
authors.initials: C
authors.lastname: Feng
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.forename: Jiulin
authors.initials: J
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle; D004265:DNA Helicases / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D055785:Gene Knockdown Techniques; D017403:In Situ Hybridization; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish / Q000196:embryology*
chemical_list: D017931:DNA Primers; D004265:DNA Helicases