L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome.
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.
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Baoshan
B
Xu
Stowers Institute for Medical Research, Kansas City, MO 64110, USA, Medical Faculty, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Nenja
N
Sowa
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27708, USA.
Maria E
ME
Cardenas
Stowers Institute for Medical Research, Kansas City, MO 64110, USA, Department of Biochemistry and Molecular Biology, University of Kansas School of Medicine, Kansas City, KS 66160, USA, jeg@stowers.org.
Jennifer L
JL
Gerton
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D003635:De Lange Syndrome / Q000188:drug therapy* / Q000196:embryology / Q000235:genetics; D004195:Disease Models, Animal; D007930:Leucine / Q000627:therapeutic use*; D009154:Mutation; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics; D000097722:Cohesins
D018797:Cell Cycle Proteins; D007930:Leucine; D058570:TOR Serine-Threonine Kinases; D029961:Zebrafish Proteins; C570219:nipblb protein, zebrafish; D000097722:Cohesins; C000598009:rad21a protein, zebrafish