Blood, 1 September 2001, Vol. 98, No. 5, pp. 1279-1279
Decay and antidecay in mammalian development: clues to
transcript abundance in the RNA world?
In 1986, Gray Shaw and Robert Kamen described an elegant set of
experiments that identified a functional element in the 3' untranslated
region of GM-CSF mRNA (Cell. 46:659-667), a region that Caput et al
(Proc Natl Acad Sci U S A. 1986;91:1318-1322) identified as being
highly conserved in transcripts that specified proteins involved in the
inflammatory response. This AU-rich region (AURE) contained repeated
clusters, sometimes concatenations, of the sequence AUUUA, and marked
any transcript to which it was attached for rapid destruction in
mammalian cells. Probably in part because these sequences are so highly
conserved (in sea urchins, for example; Asson-Batres et al, Proc Natl
Acad Sci U S A. 1994;91:1318-1322), Houzet and colleagues (page 1281)
reasoned that there might exist regulatory mechanisms governing
transcript abundance during development. The group observed that
enforced expression of wild-type GM-CSF mRNA was tolerated by E14
embryos but enforcement of deletion mutants of GM-CSF transcripts that
had no AURE was lethal at E14 (the lethality resulting from
overproduction of phagocytes owing to accumulation of GM-CSF mRNA).
Later, at E18, even the wild-type GM-CSF mRNA accumulated at high
levels and was similarly lethal.
These important observations on the ontogeny of RNA degradation may be
clues to the evolution of inducible responses in the RNA world. In
projecting how this world worked, much attention has been paid to the
function of catalytic RNA and less to mechanisms that might provide for
dynamic fluctuations in transcript abundance (without transcriptional
control to fall back on). Which came first? Did the AURE transcripts
and ribonucleases evolve before the appearance of ribonuclease
inhibitory factors? Probably, because in ontogeny some antidecay
factor evolved only after an AURE-targeted ribonucleolytic mechanism
had been well established for at least 4 days and probably more. No
doubt these experiments will lead to others that will define the
critical molecular events that evolve between days E14 and E18, events
that may clarify some of the difficult questions we have struggled with
for more than 15 years in the field of inflammation and granulopoiesis.
Grover C. Bagby, Jr
Oregon Health Sciences University Cancer Institute
