Studies of experimental motor neuron degeneration attributable to expression of neurofilament light chain (NF-L) transgenes have raised the possibility that the neuropathic effects result from overexpression of NF-L mRNA, independent of NF-L protein effects . The present study was undertaken to test for an RNA-mediated pathogenesis. Transgenic mice were derived using either an enhanced green fluorescent protein reporter construct or modified chimeric constructs that differ only in their 3′ untranslated regions (UTRs). Motor function and spinal cord histology were normal in mice expressing the unmodified reporter transgene. In mice expressing a chimeric transgene in which sequence of NF-L 3′ UTR was inserted into the 3′ UTR of the reporter transgene, we observed growth retardation and reduced kinetic activity during postnatal development. Older mice developed impairment of motor function and atrophy of nerve fibers in the ventral roots. A similar but more severe phenotype was observed when the chimeric transgene contained a 36 bp c-myc insert in an mRNA destabilizing element of the NF-L sequence. Our results suggest that neuropathic effects of overexpressing NF-L can occur at the level of transgene RNA and are mediated by sequences in the NF-L 3′ UTR.