Genetic Control of Nematode Development 
H. Robert Horvttz, Ph.D. — Investigator 
Dr. Horvitz is also Professor of Biology at the Massachusetts Institute of Technology and Neurobiologist 
and Geneticist at Massachusetts General Hospital, Boston. He earned his undergraduate degrees in 
mathematics 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 laboratory of Molecular Biology, Cambridge, England. Dr. Horvitz is a member of the National 
Academy of Sciences. 
HOW do genes control animal development? 
Taking a primarily genetic approach to an- 
swer this question, members of our laboratory 
have isolated developmental mutants of the 
roundworm Caenorhabditis elegans and have 
used both genetic and molecular genetic tech- 
niques to characterize these mutants. Because the 
complete cellular anatomy (including the com- 
plete wiring diagram of the nervous system) and 
the complete cell lineage of C. elegans are 
known, mutant animals 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 some 
cell lineage genes is constrained to a single cell 
type, tissue, or organ. For example, one gene acts 
only in the nervous system, and another acts only 
in the hypodermis. Other genes act in multiple 
tissues. 
We have analyzed a number of these genes at 
the molecular level. These studies have revealed 
that many genes that control 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. Another gene in the vul- 
val signaling pathway has similarities to the src 
gene, which is also associated with human 
cancers. The study of these and other genes that 
function in cell signaling in C. elegans might 
provide insights relevant to cancerous 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 
might be of medical importance, as the clinical 
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- 
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