Genetic Control of Nematode Development 
H. Robert Horvitz, Ph.D. — Investigator 
Dr. Horvitz is also Professor of Biology at the Massachusetts Institute of Technology and Neurobiologist 
and Geneticist at the Massachusetts General Hospital. He earned his undergraduate degrees in mathemat- 
ics and in economics at the Massachusetts Institute of Technology, followed by the M.A. and Ph.D. degrees 
in biology from Harvard University. His postdoctoral research was done at the Medical Research Labora- 
tory of Molecular Biology, Cambridge, England. Dr. Horvitz was recently elected to the National Academy 
of Sciences. 
HOW do genes control animal development? 
Taking a primarily genetic approach to this 
question, the members of our laboratory have iso- 
lated developmental mutants of the roundworm 
Caenorhabditis elegans and have used both ge- 
netic and molecular genetic techniques to charac- 
terize these mutants. Because the complete cellu- 
lar anatomy (including the complete wiving 
diagram of the nervous system) and the complete 
cell lineage of C. elegans are known, mutant ani- 
mals can be studied at the level of single cells and 
even single synapses. Genes that play specific 
roles in cell lineage, cell signaling, cell death, 
and cell migration have been identified and 
analyzed. 
Cell Lineage 
The problem of cell lineage — how a single fer- 
tilized egg cell undergoes a complex pattern of 
cell divisions to generate a multiplicity of dis- 
tinct cell types — is one major focus of the re- 
search of our laboratory. We have identified 
hundreds of genes responsible for controlling 
aspects of the C. elegans cell lineage. Many of 
these genes 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, and 
one gene acts to make certain daughter cells dif- 
ferent from their mothers. The action of many 
cell lineage genes is not constrained to a single 
tissue or organ. For example, one gene acts in 
both the nervous system and the musculature, 
while another acts in these two tissues as well as 
in the gonad and the hypodermis. 
We have analyzed a number of these genes at 
the molecular level. These studies have revealed 
that genes that control aspects of cell lineage in 
C. elegans are strikingly similar to genes found in 
other organisms, including humans. Thus the 
analysis of developmental control genes in C. ele- 
gans should help us to understand aspects of the 
development of more complex organisms. 
Cell Signaling 
Much of the development of C. elegans, like 
that of other organisms, involves intercellular 
communication. We have studied cell interac- 
tions in nematode development by using a laser 
microbeam to kill single cells in living animals: if 
destruction of one cell alters the fate of a second 
cell, the first cell must normally interact with the 
second. We have analyzed in detail the cell inter- 
actions involved in inducing the development of 
the vulva, which forms the external genitalia, 
connects the uterus with the outside environ- 
ment, and is used for egg laying and copulation. 
We have characterized many genes that function 
in the cell interactions of vulval development. 
One gene that acts as a switch in the vulval induc- 
tive signaling pathway is a member of the ras 
gene family. Other ras genes are associated with 
many human cancers; the same mutations that 
cause extra vulval cell divisions in C. elegans are 
oncogenic in mammals. The study of this and 
other genes that function in cell signaling in C. 
elegans might provide insights relevant to cancer- 
ous growth in humans. 
Cell Death 
Naturally occurring or "programmed" cell 
death is common during the development of the 
nervous system of many animals, including C. 
elegans. Why organisms generate cells only to 
have them die is an intriguing question. Further- 
more, the mechanisms responsible for cell death 
may be of some medical importance, as the clini- 
cal features of many human disorders (including 
trauma, stroke, and a variety of neurodegenera- 
tive diseases) are a consequence of nerve cell 
deaths. 
We have been identifying and characterizing 
genes that function in programmed cell death in 
C. elegans. Two genes cause cells to die, and 
seven other genes are involved in removing the 
corpses of dead cells. The two genes that cause 
cells to die must be expressed by the dying cells 
themselves, indicating that, at least to this extent, 
programmed cell deaths are cell suicides. Al- 
though many cells die during the course of C. 
e/egflns development, most cells survive; cell sur- 
vival requires the inactivation of the cell death 
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