IBN 98-10803 TWISS. Gene expression, in which a cells genes are turned on and become active, is a tightly regulated process whereby the genetic codes of DNA in the nucleus is "transcribed" into an intermediate messenger compound, RNA, which is then "translated" to produce a given protein. Gene transcription is a complex and highly controlled mechanism. Cellular type is determined by the specific combination of proteins which a cell expresses. Therefore, once a messenger RNA molecule is produced it still must be translated into protein to have any effect. It has become increasingly clear that this translation of messenger RNA into protein can also be regulated. Translational control of preexisting messenger RNAs is indeed an efficient and rapid mechanism to alter cellular protein levels. Initial studies have shown that cells of the nervous system can control the translation of messenger RNAs to rapidly respond to extracellular stimuli (stimuli outside the cell) and injury. Although, translationally-regulated messenger RNAs are known in other cell types, until recently, no specific messenger RNAs that are regulated in this fashion have been identified in neurons. Dr. Twiss has isolated a messenger RNA whose translation is regulated by a chemical known as "nerve growth factor" during neuronal differentiation (transition from a precursor cell into a maturee nerve cell) and regeneration (repair following injury). This messenger RNA encodes for a particular component of translational machinery, a protein associated with the translation centers, "ribosomes." Preliminary studies have shown that differentiated neurons distinctly regulate translation of this ribosomal protein messenger RNA in different growth states. Translation of this ribosomal protein mRNA is required for some forms of neuronal regeneration. Using an in vitro model of neuronal differentiation and regeneration, Dr. Twiss will investigate the role of this ribosomal protein in mature and injured neurons and how it affects the function of the translational machinery. The goal of these experiments is to elucidate the fundamental biological mechanisms and consequences of translational regulation in neurons. The experiments proposed will advance the understanding of this increasingly important basic neuronal response and will be the first to specifically address the mechanisms and impact of translational control in neurons.
