DEVELOPMENTALLY-REGULATED ALTERNATIVE SPLICING OF MESSENGER-RNAS ENCODING N-TERMINAL TAU-VARIANT IN THE RAT HIPPOCAMPUS - STRUCTURAL AND FUNCTIONAL IMPLICATIONS

Tau protein variants are axonal microtubule-associated phosphoproteins whose expression correlates with developmentally regulated neurite ou tgrowth. A single gene encodes multiple tau transcripts via complex al ternative splicing. We studied the expression of the mRNAs encoding N- terminal variants of tau, and we showed distinct alternative splicing of exons 2 and 3 in nervous tissues of the adult rat, including the in ner ear, hippocampus, cortex, striatum, brainstem, cerebellum, olfacto ry bulb and retina. Using the reverse transcriptase-coupled polymerase chain reaction and in situ hybridization, we then focused our develop mental study on hippocampal neurons, both in vivo and in vitro, to add ress the developmental and spatial expression of the alternatively spl iced mRNAs encoding N-terminal variants of tau. Tau mRNAs devoid of ex ons 2 and 3 were present throughout development, although their levels decreased in adults. Those containing exon 2 but not exon 3 were alre ady present in the hippocampus of newborn rats and their levels increa sed during the first postnatal week, mainly in the pyramidal cell laye r. Tau RNAs containing exons 2 and 3 appeared at the end of this perio d in the pyramidal cell layer and in the dentate granule cells. Exon 2 -containing mRNAs seemed to be associated with cells undergoing axonal sprouting, while exon 3-containing RNAs were expressed in mature neur ons that had established their connections. The timing and pattern of tau alternative splicing were maintained in cultured hippocampal neuro ns, suggesting that splicing processes are independent of the organize d connectivity and of the environmental cues provided in vivo. Seconda ry structure predictions of tau variants revealed that the insertion o f the exon 3-encoded domain substantially modifies the secondary struc ture of the N-terminal region of tau. This N-terminal heterogeneity ma y confer distinct regulatory roles on the tau variants during ontogeny and may contribute to plasticity in the adult rat brain.