Determination and Maintenance of Cell Type 
Richard H. Gomer, Ph.D. — Assistant Investigator 
Dr. Gomer is also Assistant Professor of Biochemistry and Cell Biology at Rice University and Adjunct As- 
sistant Professor of Cell Biology at Baylor College of Medicine. He received his B.A. degree in physics from 
Pomona College and his Ph.D. degree in biology from the California Institute of Technology, where he 
studied with Elias Lazarides. He was a postdoctoral fellow in the laboratory of Richard Firtel at the Uni- 
versity of California, San Diego. 
OUR laboratory is interested in the general 
problem of differentiation and morphogen- 
esis. We are trying to understand at a molecular 
level some of the factors that determine the cell 
type into which an embryonic cell differentiates 
and how the ratios of the different cell types are 
then maintained in an organism. As a model sys- 
tem, we are using the slime mold Dictyostelium 
discoideum. 
Dictyostelium normally exists as undifferen- 
tiated single cells called amoebae that eat bacte- 
ria in soil and decaying leaves and proliferate by 
cell division. When the amoebae eventually over- 
grow their food supply and starve, they aggregate 
together in groups of about 100,000. Roughly 80 
percent of these cells become spores. (A spore is 
a cell with a tough outer coat that forms an 
"escape capsule.") The remaining 20 percent of 
the cells form a stalk about 2 mm high that holds 
the spore cells off the ground. A spore, dispersed 
by the wind, will crack open to release an 
amoeba, which may luckily find itself in the 
midst of a new supply of bacteria. The advantage 
of this organism is its simplicity: cells differen- 
tiate into just two main types. 
Determining Cell Fate 
In the presence of a food source, Dictyoste- 
lium cells grow to a certain size and then separate 
their chromosomes to opposite sides of the cell 
and divide in two. The cycle of grov^h and divi- 
sion then repeats. In a field of cells, there will be 
cells at all different phases of this cycle. 
Dictyostelium uses a simple and elegant mech- 
anism based on this cycle to determine whether a 
cell will become stalk or spore. When the cells 
starve, those cells that have recently separated 
their chromosomes and divided will become 
stalk cells, and the remaining cells become 
spores. As long as the cells are randomly distrib- 
uted with respect to the phase of their cell cycles, 
there will always be the proper percentage of 
cells in the "stalk" quadrant. We refer to this as a 
musical chairs mechanism, since the decision of 
any given cell to become either stalk or spore is 
made by the phase of the cycle that the cell hap- 
pens to be in at the time of the differentiation 
signal (starvation). 
Cell-type choice determination mechanisms of 
this sort may operate in humans, and aberrations 
could thus lead to birth defects. We are presently 
mutating Dictyostelium cells and isolating mu- 
tants with altered cell-type ratios. We will then 
use DNA transformation to identify the genes that 
were mutated. We are also using drugs that 
disrupt the cell cycle to examine the extent of the 
linkage between the cell cycle and cell-type 
choice. 
Sensing Cell Density 
During Dictyostelium development, a cell 
waits until it is near a large mass of other Dictyo- 
stelium cells before it turns on the stalk- or 
spore-specific genes. Being able to sense whether 
other cells are nearby represents a paradigm 
for possible mechanisms that would allow, for 
instance, liver cells to sense how much of the 
body is composed of liver cells. At present, little 
is known about the molecular mechanisms 
whereby the size and density of a tissue are sensed 
by its individual cells. Such mechanisms would 
be centrally involved in the regulation of growth 
during development, wound healing, and regen- 
eration. In addition, an important and relevant 
aspect of tumor cells is that they have lost their 
ability to regulate the size and/or density of the 
tissue and, as a result, proliferate. One way this 
could happen would be if the tumor cells could 
no longer properly sense the total mass of the 
tissue. 
We have found that Dictyostelium cells sense 
whether they are near other cells by secreting 
small quantities of a protein, which we have 
named density-sensing factor (DSF). Cells are 
sensitive to DSF: above a threshold concentration 
they will express cell-type-specific genes. We 
have done theoretical diffusion calculations and 
have found, in agreement with our observations, 
that DSF secreted from cells that are quite far 
from other cells diffuses away so quickly that it 
never reaches the threshold concentration. How- 
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