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Abstract
In amphibian limb regeneration memory for position in the proximal-distal axis can
be respecified by retinoic acid. The favoured candidates to mediate this effect are
the retinoic acid receptors (RARs) and of the RARs identified in the regeneration
blastema, the delta receptor is the most abundant. The presence in blastemal mesenchyme
of at least two delta receptor isoforms, delta 1 and delta 2, alternatively spliced
at the A-B junction, was demonstrated in expression studies and by PCR cloning. The
delta 1 receptor is abundant in regenerative structures such as the limb and tail,
whereas the delta 2 and alpha receptors show a more uniform pattern of expression
across adult newt tissues. Full-length cloning of the delta 1 receptor established
the presence of an unusually long open reading frame and N-terminal sequence that
appears unique among vertebrate retinoic acid receptors. Transient transfection of
expression constructs into COS cells followed by Western blotting confirmed the existence
of at least three potential initiation sites for delta 1 translation. The possibility
that delta 1 RAR expression may specify positional memory directly was tested in RNase
protection experiments. delta 1 receptor message is increased on amputation, but does
not exhibit a pronounced differential distribution along the proximal-distal axis
in normal and regenerating limbs, nor does it show a persistent alteration in expression
levels following a dose of retinoic acid sufficient to respecify position. The possibility
that the morphogenetic effects of RA may be mediated through receptor interactions
is raised by the finding that single mesenchymal blastemal cells in culture can express
multiple RAR subtypes (delta 1 and alpha) and isoforms (delta 1 and delta 2).