Cell Lineage, Cell Fate and MicroRNAs

We have identified numerous genes that control cell lineage and cell fate during C. elegans development. Many of these genes encode proteins similar to known transcription factors, and our studies indicate that the generation of cell diversity during development is in part regulated by a cascade of interacting transcription factors. Because two heterochronic genes, which control the developmental timing of cell lineage and cell fate, encode the founding members of a novel 21-22 nt family of regulatory RNAs found in all animals examined to date, we have initiated a genomics/robotics project to analyze the more than 100 such microRNAs encoded by the C. elegans genome. To date, we have isolated deletion mutations of 57 of these microRNA genes. These mutants have indicated that microRNAs can act redundantly to control developmental timing and other biological processes. We have also begun studies of mammalian microRNAs. We have developed a mammalian micro-RNA microarray, used it to determine the microRNA expression profile during mouse brain development and observed a temporal wave of gene expression of sequential classes of microRNAs.

One of the first cell lineage mutants we characterized defined the gene lin-4. This gene was the founding member of a set of genes that control aspects of developmental timing. Since mutations in these genes cause temporal transformations in cell fates, we named these genes "heterochronic." The heterochronic gene we discovered most recently was let-7, which we identified in our studies of mutants abnormal in the development of the serotonergic HSN neurons, which drive egg laying. lin-4 and let-7 do not encode proteins but rather encode small 21-22 nt RNAs, termed micro RNAs, and act by binding the mRNAs of target genes and preventing translation. We have recently embarked upon a collaborative project with MIT colleague David Bartel and our ex-postdoctoral fellow Victor Ambros to characterize the complete set of more than 100 MICRO RNAs in the C. elegans genome.

We are currently analyzing the genetic control of the fate of a specific neuron type, the CEM. The four male-specific CEM neurons, which are suspected to help the male chemotax toward hermaphrodites, are generated in both males and hermaphrodites but undergo programmed cell death in hermaphrodites. We are isolating and characterizing mutants in which the CEMs fail to die in hermaphrodites and in this way are defining genes that control both the specification of CEM cell fate and the decision between survival and the alternative fate of Programmed cell death (apoptosis).