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.