Our data indicate that intracardiac flow dynamics regulate valve morphogenesis independently of myocardial contractility.

Charcot-Marie-Tooth (CMT) disease is a genetically heterogeneous group of peripheral neuropathies. Mutations in several aminoacyl-tRNA synthetase (ARS) genes have been implicated in inherited CMT disease. There are 12 reported CMT-causing mutations dispersed throughout the primary sequence of the human glycyl-tRNA synthetase (GARS). While there is strong genetic evidence linking GARS mutations to CMT disease, the molecular pathology underlying the neuromuscular and sensory phenotypes is still not fully understood. In particular, it is unclear whether the mutations result in a toxic gain of function, a partial loss of activity related to translation, or a combination of these mechanisms. We identified a zebrafish allele of gars (gars(s266)). Homozygous mutant embryos carry a C->A transversion, that changes a threonine to a lysine, in a residue next to a CMT-associated human mutation. We show that the neuromuscular phenotype observed in animals homozygous for T209K Gars (T130K in GARS) is due to a loss of dimerization of the mutated protein. Furthermore, we show that the loss of function, dimer-deficient and human disease-associated G319R Gars (G240R in GARS) mutant protein is unable to rescue the above phenotype. Finally, we demonstrate that another human disease-associated mutant G605R Gars (G526 in GARS) dimerizes with the remaining wild-type protein in animals heterozygous for the T209K Gars and reduces the function enough to elicit a neuromuscular phenotype. Our data indicate that dimerization is required for the dominant neurotoxicity of disease-associated GARS mutations and provide a rapid, tractable model for studying newly identified GARS variants for a role in human disease.

Long non-coding RNAs (lncRNAs) constitute one of the most broad and diverse classes of cellular transcripts, playing key roles as regulatory molecules in many biological processes. Although the biology of lncRNAs is a new and emerging field of research, several studies have already shown that alterations in the expression of lncRNAs are associated with the development and progression of cancer in different organs and tissues, including central and peripheral nervous system. In this review, we summarize the oncogenic and tumor suppressive roles of lncRNAs in malignant tumors of the nervous system, such as glioma and neuroblastoma, focusing on their functional interactions with DNA, other RNA and protein molecules. We further discuss the potential use of lncRNAs as biomarkers for diagnosis, prognosis and tumor treatment. Gaining insight into the functional association between nervous system malignancies and lncRNAs could offer new perspectives to the development of promising therapeutic tools against cancer.