Abstract
High levels of neurofilament (NF) mRNA expression are attained during early postnatal development and are a major determinant of axonal size. High level NF expression is also dependent upon axonal continuity since NF mRNA levels are down-regulated after nerve transection. This study shows that both postnatal up-regulation and axotomy-induced down-regulation are altered by deletion of 3'-UTR from the mouse light NF subunit (NF-L). Transgenes with (NF-L+) or without (NF-L-) 3'-UTR display similar patterns of neuron-specific expression but differ in their respective levels of expression. Whereas changes in the level of NF-L+ mRNA parallel those of the endogenous mouse NF-L mRNA, changes in the level of NF-L- mRNA differ from the pattern of endogenous NF-L expression during postnatal up-regulation and axotomy-induced down-regulation. Specifically, the NF-L- transgene undergoes a 3-fold aberrant up-regulation between embryonic days 15 (E15) and 18 (E18) and has lost its susceptibility to axotomy-induced down-regulation. Studies of transfected P19 cells show that 3'-UTR deletion leads to a severalfold stabilization of NF-L mRNA and an increase in steady-state mRNA level. The findings support the working hypothesis that the 3'-UTR contains determinants that alter stability and that stabilization of NF-L mRNA regulates the levels of NF-L mRNA in neuronal tissues and cells.
Highlights
Lead to proximal NF accumulations and to reduced NF content and size of distal axons
The NF-L transgenes contained an insert at the BglII site (ϩ829) that enables transcripts from the transgenes and endogenous mouse NF-L gene to be distinguished by RNase protection assay
Levels of NF-LϪ mRNA are higher than NF-Lϩ mRNA in stably transformed P19 cells even though the lines were derived from pooled transformants and contained similar average copy numbers of the respective transgenes (5–10 copies/pool)
Summary
Lead to proximal NF accumulations and to reduced NF content and size of distal axons. The postnatal surge of NF expression correlates closely with increases of NF content and with enlargements of perikaryal size and axonal caliber [13]. The same NF transcripts in adult sensory neurons are destabilized in vitro in a transcription-dependent manner [15] by a process that resembles the coordinated down-regulation of NF mRNAs following axotomy [16]. These findings have led to the view that NF mRNAs are stabilized in high-expressing neurons and that changes in mRNA stabilities may account for the coordinate up-regulation and down-regulation of NF mRNA levels that occur during postnatal development and in axotomized neurons, respectively. The findings indicate the importance of 3Ј-UTR in NF-L expression and highlight the potential role of posttranscriptional mechanisms in regulation of neuron-specific gene products
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