GENETIC CONTROL OF NEMATODE DEVELOPMENT 
H. Robert Horvitz, Ph.D., Investigator 
How do genes control animal development? Tak- 
ing a primarily genetic approach to answer this 
question, Dr. Horvitz and his colleagues have iso- 
lated developmental mutants of the nematode 
Caenorhabditis elegans and have used genetic and 
molecular genetic techniques to characterize these 
mutants. Because the complete ultrastructure (in- 
cluding the complete 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. In this 
way, genes involved in cell lineage, cell death, cell 
migration, and cell differentiation have been identi- 
fied and analyzed. 
L Cell Lineage. 
The problem of cell lineage— how a single fertil- 
ized egg cell undergoes a complex pattern of cell 
divisions to generate a multiplicity of distinct cell 
types— is one major focus of the research of this 
laboratory. Hundreds of cell lineage mutations have 
been identified that cause certain cells to express 
lineages or fates normally associated with certain 
other cells. For example, a mutation in the newly 
identified gene lin-44 causes certain sister cells that 
normally differ in their fates to be reversed in their 
fates. Mutations in the gene lin-11 cause certain sis- 
ter cells that normally differ in their fates to express 
the same fate. The DNA sequence of lin-11 suggests 
that the lin-11 protein contains two DNA-binding 
domains (a homeodomain and a zinc-binding do- 
main) as well as a domain involved in protein-pro- 
tein interactions (a proline-rich domain). Mutations 
in the gene unc-86 cause certain daughter cells to 
express the fates of their mother cells. The DNA se- 
quence of unc-86 reveals that the unc-86 protein is 
strikingly similar over a region of ~160 amino acids 
to three mammalian transcription factors (Pit-1 and 
the octamer-binding proteins Oct-1 and Oct-2), 
which has led to the name of the common POU 
motif {pit, oct, unc) and to the suggestion that 
these mammalian genes not only regulate gene 
expression but also specify cell fates during devel- 
opment. 
The cell lineages of vulval development, which 
are determined via cell-cell interactions, have been 
analyzed in some detail. A genetic pathway for vul- 
val development that now consists of 46 genes has 
been defined. Most of these genes participate in the 
determination of the fates of the vulval precursor 
cells. Of the determination genes, lin-10 has been 
studied most extensively. Combined molecular and 
genetic analyses have indicated that this gene en- 
codes a 45 kDa polypeptide that acts within the cy- 
toplasm of the vulval precursor cells to transduce 
information from a membrane receptor to the nu- 
cleus. Despite the highly limited temporal and spa- 
tial localization of lin-10 function as defined geneti- 
cally, lin-10 mRNA and protein are expressed very 
broadly. It is possible that it is the specificity of 
expression of other genes involved in vulval de- 
velopment that leads to the specificity of function 
of lin-10. 
II. Cell Death. 
Naturally occurring or "programmed" cell death 
is common during the development of many ani- 
mals, including C. elegans. Dr. Horvitz and his col- 
leagues have identified and characterized geneti- 
cally and molecularly two genes, ced-3 and ced-4, 
that are necessary for the initiation of programmed 
cell death. Six additional genes {ced-1, -2, -5, -6, -7, 
and -8), four of which are newly discovered, are 
necessary for the corpse of a cell undergoing pro- 
grammed cell death to be engulfed by a neighbor- 
ing cell. Analysis of these genes may reveal the mo- 
lecular mechanisms responsible for this specific 
cell-cell interaction. A number of mutations have 
been identified that cause cells to die that normally 
survive. Some of these mutations cause the ectopic 
activation of ced-3 and ced-4, whereas others result 
in the cytotoxic expression of particular gene prod- 
ucts. Because cell death is the cause of the major 
clinical features of human neurodegenerative dis- 
eases, human homologues of C. elegans cell death 
genes are being sought. In addition, linkage analy- 
sis of familial amyotrophic lateral sclerosis (ALS or 
Lou Gehrig disease) has been begun in an attempt 
to initiate molecular genetic studies of human dis- 
eases caused by cell death. 
III. Cell Migration. 
Animal development involves cell migrations. To 
understand what causes cells both to migrate and 
to stop migrating, this laboratory has analyzed a 
number of C. elegans cell migrations. For example, 
the two sex myoblast (SM) cells, which are born in 
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