The heterochronic genes
lin-14 and
lin-28 coordinate the timing of developmental events in early larval stages. If either activity is reduced then precocious expression of L3-specific events occurs in the L2. Because these genes act in diverse cell types to control a variety of cell division and differentiation events, they may act on diverse targets or on just a few that in turn have diverse affects. Mutations in
lin-46 completely suppress
lin-28 loss-of-function alleles and
lin-14 hypomorphs. To our surprise, null mutations in
lin-46 suppress null mutations in
lin-28 to the wildtype phenotype. This immediately raises two questions: Might
lin-46 be one of several targets of
lin-28 ? and What can
lin-46 tell us about the relationship between
lin-14 and
lin-28 ? Several experiments have delivered more questions than answers. By GFP fusion assay,
lin-46 appears to be expressed exclusively in two bilaterally symmetric AV interneurons and this expression is not temporally regulated. This is in contrast to
lin-14 and
lin-28 , which are expressed ubiquitously in the L1 and then repressed. A precocious phenotype can result from
lin-46 trangenes in a wildtype background, indicating that the level of
lin-46 is important in heterochronic regulation.
lin-46 mutations can suppress all alleles of
lin-28 , hypomorphs of
lin-14 , but not null alleles of
lin-14 . Mutant combinations suggest that
lin-46 does not act by raising the level of an activity upstream of
lin-14 or
lin-28 . Curiously, a
lin-46 mutation appears unable to suppress the double mutant
lin-42 ;
lin-14(ts) , two mutations it can suppress separately, suggesting there is an important relationship among these genes.
lin-46 encodes a member of the moeA family, which includes vertebrate gephyrin and a molybdopterin synthesis pathway component. These homologies suggest nothing more than the LIN-46 protein may interact with other proteins to carry out its function. Perhaps LIN-46 is a component of a multi-protein complex, whose components are targets of
lin-28 negative regulation, so that a null mutation in
lin-46 can reduce the output of the pathway without eliminating it.