Department of Biology
Massachusetts Institute of Technology
Howard Hughes Medical Institute
McGovern Institute for Brain Research


Research: Cell Lineage

and Cell Fate

The problem of cell lineage -- how a single fertilized egg cell undergoes a complex pattern of cell divisions to generate a multiplicity of distinct cell types -- has been a long-term interest of our laboratory. We have identified hundreds of mutations that affect the nearly invariant and completely described C. elegans cell lineage. Many of the genes defined by these mutations function in generating cell diversity during development. For example, some genes act to make the two daughter cells generated by a single cell division different from each other. Others control spatial patterning. Many genes that control the C. elegans cell lineage encode proteins similar to known transcription factors (e.g., unc-86 and lin-11, founding members of the POU and LIM protein families, respectively), and our studies indicate that the generation of cell diversity during development is in part regulated by a cascade of interacting transcription factors.

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).

Publications: Cell Lineage and Cell Fate

Abstracts: Cell Lineage and Cell Fate

The Horvitz Lab