TY - JOUR
T1 - Untranslated element in neurofilament mRNA has neuropathic effect on motor neurons of transgenic mice
AU - Nie, Zhenying
AU - Wu, Junhua
AU - Zhai, Jinbin
AU - Lin, Hong
AU - Ge, Weiwen
AU - Schlaepfer, William W.
AU - Cañete-Soler, Rafaela
PY - 2002/9/1
Y1 - 2002/9/1
N2 - 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 (Cañete-Soler et al., 1999). 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.
AB - 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 (Cañete-Soler et al., 1999). 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.
KW - EGFP reporter transgene
KW - Motor neuron degeneration
KW - Neurofilament-induced
KW - Neuropathic RNA element
KW - RNA-mediated
KW - Transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=0036759174&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036759174&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.22-17-07662.2002
DO - 10.1523/jneurosci.22-17-07662.2002
M3 - Article
C2 - 12196589
AN - SCOPUS:0036759174
SN - 0270-6474
VL - 22
SP - 7662
EP - 7670
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 17
ER -