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L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome.

Publication ,  Journal Article
Xu, B; Sowa, N; Cardenas, ME; Gerton, JL
Published in: Hum Mol Genet
March 15, 2015

Cohesinopathies are human genetic disorders that include Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) and are characterized by defects in limb and craniofacial development as well as mental retardation. The developmental phenotypes of CdLS and other cohesinopathies suggest that mutations in the structure and regulation of the cohesin complex during embryogenesis interfere with gene regulation. In a previous project, we showed that RBS was associated with highly fragmented nucleoli and defects in both ribosome biogenesis and protein translation. l-leucine stimulation of the mTOR pathway partially rescued translation in human RBS cells and development in zebrafish models of RBS. In this study, we investigate protein translation in zebrafish models of CdLS. Our results show that phosphorylation of RPS6 as well as 4E-binding protein 1 (4EBP1) was reduced in nipbla/b, rad21 and smc3-morphant embryos, a pattern indicating reduced translation. Moreover, protein biosynthesis and rRNA production were decreased in the cohesin morphant embryo cells. l-leucine partly rescued protein synthesis and rRNA production in the cohesin morphants and partially restored phosphorylation of RPS6 and 4EBP1. Concomitantly, l-leucine treatment partially improved cohesinopathy embryo development including the formation of craniofacial cartilage. Interestingly, we observed that alpha-ketoisocaproate (α-KIC), which is a keto derivative of leucine, also partially rescued the development of rad21 and nipbla/b morphants by boosting mTOR-dependent translation. In summary, our results suggest that cohesinopathies are caused in part by defective protein synthesis, and stimulation of the mTOR pathway through l-leucine or its metabolite α-KIC can partially rescue development in zebrafish models for CdLS.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

March 15, 2015

Volume

24

Issue

6

Start / End Page

1540 / 1555

Location

England

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • TOR Serine-Threonine Kinases
  • Protein Biosynthesis
  • Phosphorylation
  • Mutation
  • Leucine
  • Genetics & Heredity
  • Disease Models, Animal
  • De Lange Syndrome
 

Citation

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Xu, B., Sowa, N., Cardenas, M. E., & Gerton, J. L. (2015). L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome. Hum Mol Genet, 24(6), 1540–1555. https://doi.org/10.1093/hmg/ddu565
Xu, Baoshan, Nenja Sowa, Maria E. Cardenas, and Jennifer L. Gerton. “L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome.Hum Mol Genet 24, no. 6 (March 15, 2015): 1540–55. https://doi.org/10.1093/hmg/ddu565.
Xu, Baoshan, et al. “L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome.Hum Mol Genet, vol. 24, no. 6, Mar. 2015, pp. 1540–55. Pubmed, doi:10.1093/hmg/ddu565.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

March 15, 2015

Volume

24

Issue

6

Start / End Page

1540 / 1555

Location

England

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • TOR Serine-Threonine Kinases
  • Protein Biosynthesis
  • Phosphorylation
  • Mutation
  • Leucine
  • Genetics & Heredity
  • Disease Models, Animal
  • De Lange Syndrome