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.