Upregulation of the let-7 microRNA with precocious development in lin-12/Notch hypermorphic C. elegans mutants

The lin-12 /Notch signaling pathway is conserved from worms to humans and is a master regulator of metazoan development. Here, we demonstrate that lin-12 /Notch gain-of-function ( gf ) animals display precocious alae at the L4 larval stage with a significant increase in let-7 expression levels. Furthermore, lin-12 ( gf) animals display a precocious and higher level of let-7 gfp transgene expression in seam cells at L3 stage. Interestingly, lin-12 ( gf ) mutant rescued the lethal phenotype of let-7 mutants similar to other known heterochronic mutants. We propose that lin-12 /Notch signaling pathway functions in late developmental timing, upstream of or in parallel to the let-7 heterochronic pathway. Importantly, the human microRNA let-7a was also up-regulated in various human cell lines in response to Notch1 activation, suggesting an evolutionarily-conserved cross-talk between let-7 and the canonical lin-12 /Notch signaling pathway.