DEVELOPMENTAL REGULATION OF NEUROTROPHIN-3 AND TRK-C SPLICE VARIANTS IN OPTIC-NERVE GLIA IN-VIVO

Extensive evidence indicates that the survival and development of neur ons is dependent on neurotrophins. However, the factors potentially re quired for glial development and function, and the sites of synthesis, are not well defined. To investigate the potential role of neurotroph ins in glial development in vivo, we studied the trk Family of recepto rs and their cognate neurotrophins in the postnatal rat optic nerve us ing reverse transcription-polymerase chain reaction. Our results indic ate that trk A, B and C messenger RNAs are expressed throughout develo pment, and in adulthood. Both trk B and trk C expression decreased dur ing development. However, trk C expression decreased most markedly, re aching barely detectable levels by day 90. These findings suggest that neurotrophins can affect both immature and mature glial function and that their actions may be regulated through the modulation of putative receptors. To determine whether alternatively spliced forms of trk C potentially mediate neurotrophin-3 actions, we assessed expression of the different trk C isoforms. We employed reverse transcription-polyme rase chain reaction using primers that selectively amplify the extrace llular or intracellular domains. Optic nerve expressed both the full-l ength receptor and one form containing an insertion in the tyrosine ki nase domain. In addition, the expression of the insert splice variant was developmentally regulated. Our observations suggest that, in glia, actions of neurotrophin-3 are probably mediated through the full-leng th receptor and that selected alternatively spliced forms may also be involved in trk C receptor function. To determine whether glia at diff erent stages of differentiation elaborate neurotrophins, we analysed e xpression of nerve growth factor, brain-derived neurotrophic factor, n eurotrophins-3 and -4/5 in the optic nerve during development. Messeng er RNAs for all the neurotrophins were detected at all postnatal ages, suggesting that progenitor cells, immature and mature glia are potent ial sources of neurotrophins. However, neurotrophin expression was not developmentally regulated. The invariant neurotrophin messenger RNA l evels, and the changing expression of trk B and trk C during ontogeny, suggest that trophic regulation of glial development is primarily gov erned through modulation of receptor expression.