A short history of a short RNA

The intellectual backdrop motivating our effort to clone lin-4 (Lee et al., 1993) had nothing to do with questions about noncoding RNAs or antisense gene regulation. We were simply curious about an interesting worm mutant, and everything we found out about it was unexpected. We consider ourselves very lucky to happen to have chosen lin-4 to study. In fact, good fortune appeared at many steps before and during ourlin-4 project, often through the contributions of other people. lin-4 was discovered in Sydney Brenner's lab in the mid 1970s through the isolation of a mutation (e912). The remarkable developmental defects of lin-4(e912) were first described by Horvitz and Sulston (1980) and characterized in detail by Chalfie et al. (1981). lin-4(e912) animals look terrible: they grow into long, thin "adults" with a larval skin, and they fail to stop molting at the normal stage and thus undergo extra larval stages. Chalfie et el. (1981) showed that e912 hermaphrodites and males are completely missing many of the cell types and morphological structures typical of the wild-type adults, and instead contain many extra copies of cells ordinarily produced only at an early larval stage. It appeared that the e912 mutation was causing a failure of temporal developmental switches throughout the animal, indicating that lin-4 might encode a master regulator of developmental timing. For us, a particularly alluring feature of lin-4 was its genetic relationship with lin-14, lin-14 was discovered by Edwin (Chip) Ferguson, a graduate student in Bob Horvitz's lab. Chip was characterizing genetic pathways controlling steps in development of the C. elegans hermaphrodite vulva (Ferguson et al., 1987). lin-4(e912) hermaphrodites lack even a hint of a vulva (owing to their failure to generate appropriately specified vulva precursor cells) and hence are unable to lay their eggs (which consequently hatch inside their mother and consume her). While growing cultures of lin-4(e912) animals for genetic experiments, Chip serendipitously discovered a spontaneous revertant that displayed nearly normal morphology and egg-laying. Chip determined that the responsible suppressor mutation was in a previously unknown gene, lin-14. Later, Victor, as a postdoc working in the Horvitz lab, identified apparent null alleles of