6-methyl-2-(phenylethynyl)pyridine and Craniofacial-Abnormalities

Fragile X Syndrome is a leading heritable cause of mental retardation that results from the loss of FMR1 gene function. Studies in mouse and Drosophila model organisms have been critical in understanding many aspects of the loss of function of the FMR1 gene in the human syndrome. Here, we establish that the zebrafish is a useful model organism for the study of the human fragile X syndrome and can be used to examine phenotypes that are difficult or inaccessible to observation in other model organisms. Using morpholino knockdown of the fmr1 gene, we observed abnormal axonal branching of Rohon-Beard and trigeminal ganglion neurons and guidance and defasciculation defects in the lateral longitudinal fasciculus. We demonstrate that this axonal branching defect can be rescued by treatment with MPEP [2-methyl-6-(phenylethynyl) pyridine]. This is consistent with an interaction between mGluR signalling and fmr1 function in neurite morphogenesis. We also describe novel findings of abnormalities in the abundance of trigeminal ganglion neurons and of craniofacial abnormalities apparently due to dysmorphic cartilage formation. These abnormalities may be related to a role for fmr1 in neural crest cell specification and possibly in migration.

Topics: Animals; Craniofacial Abnormalities; Disease Models, Animal; Excitatory Amino Acid Antagonists; Facial Bones; Fragile X Syndrome; Humans; Morphogenesis; Neural Crest; Neurites; Oligodeoxyribonucleotides, Antisense; Pyridines; Receptors, Metabotropic Glutamate; RNA-Binding Proteins; Zebrafish; Zebrafish Proteins