that regulate cell fate determination
At the lab, we study the molecular basis that causes that
genetically identical cells, exposed to identical environment,
behave differently. We are interested in understanding the
causes of the variability that “hides” behind
the population mean. This is important to improve our understanding
of basic processes, such as the embryo development, as well
as applied issues, such as the development of new therapies
to combat disease.
Cells in an organism can behave differently
for a number of reasons. They might have sustained mutations
or genetic rearrangements, such as those that happen to produce
immunoglobulins or during oncogene amplification, or they
might have differentiated into different cell types. It is
also possible that cells might make different decisions by
chance, due to random fluctuations in the numbers of key decision-making
regulatory molecules inside cells (molecular noise). In our
lab we study these last two cases, cell differentiation and
the effect of noise. We use two model systems, the beer yeast
S.cerevisiae and human lymphocytes in culture, and we apply
a systems biology approach. In yeast, we study asymmetric
division, one of the key mechanisms that results in cell type
diversity. In this process, unequal segregation at the time
of cell division of mRNAs, proteins or other molecules important
for cell fate determination, leads to the execution of different
gene expression programs. We found that a group of genes is
expressed exclusively in one of the daughter cells and we
then found that that is caused by the asymmetric localization
of the protein that controls these genes expression, Ace2,
in only one of the nuclei. We are now studying the mechanism
that causes this asymmetry.
We also study mating pheromone response
in yeast, which activates an evolutionary well-conserved signal
transduction pathway (a G-protein coupled receptor that initiates
a MAP kinase cascade). In this system, we found large cell
to cell variability in the response. We determined that only
a small part was due to molecular noise, while an important
part was due to differences among cells in their ability to
express genes. Notably, we found that the level of variability
is under genetic control, by proteins that increase variability
and proteins that reduce variability. We are now porting the
methods and techniques we employed in yeast to the study of
interferon g response in human lymphocytes (a well conserved
Here we are very interested in determining
if the correct control of variability in response is important
to achive an appropriate immune response.
CTS1 gene promoter controlling the expression of
yellow fluorescent protein (PCTS1-YFP)
in only one of the cells.
After the completion of mitosis, the Ace2-YFP protein
fusion shuttles to the nucleus and remains
in only one of the cells. Numbers indicate time elapsed
(in minutes) since the beginning of the observation.
CF: phase contrast; DNA: DAPI nuclear staining corresponding
to time point 0.
- Gordon, A., Colman-Lerner, A., Chin, T. E., Benjamin, K. R., Yu, R. C., & Brent, R. Single-cell
quantification of molecules and rates using open-source microscope-based cytometry. Nature Methods, 4 (2) 175-181.
- Colman-Lerner, A., Gordon, A., Pesce, C. G., Serra, E., Chin, T. E., Resnekov, O., Endy, D. & Brent, R. Regulated Cell to Cell Variation in a Cell Fate Decision System. Nature 437(7059): 699-706.
- Colman-Lerner, A., Chin, T. E. and Brent, R. (2001). "Yeast Cbk1 and Mob2 activate daughter-specific genetic programs to induce asymmetric cell fates." Cell 107(6): 739-750.
- Colman-Lerner, A. and Brent, R. (2000). Using Peptide Aptamers to Analyse the Proteome. In: New Technologies for Life Sciences: A Trends Guide Special Issue 56-60.
- Geyer, C. R., Colman-Lerner, A. and Brent, R. (1999). "Mutagenesis" by peptide aptamers identifies genetic network members and pathway connections." PNAS 96(15): 8567-8572.
- Colman-Lerner, A., Fischman, M. L., Lanuza, G. M., Bissell, D. M., Kornblihtt, A. R. and Baranao, J. L. (1999). "Evidence for a role of the alternatively spliced ED-I sequence of fibronectin during ovarian follicular development." Endocrinology 140(6): 2541-8.
- Lerner, A. A., Fischman, M. L., Lanuza, G., Cramer, P., Kornblihtt, A. and Baranao, J. L. (1997). "[Role of different forms of fibronectin in in vitro bovine follicular development]." Medicina (B Aires) 57(3): 332-6.
- Lerner, A. A., Salamone, D. F., Chiappe, M. E. and Baranao, J. L. (1995). "Comparative studies between freshly isolated and spontaneously immortalized bovine granulosa cells: protein secretion, steroid metabolism, and responsiveness to growth factors." Journal of Cellular Physiology 164(2): 395-403.
- Fazzini, M., Vallejo, G., Colman-Lerner, A., Trigo, R., Campo, S., Baranao, J. L. & Saragueta, P. (2006). Transforming growth factor-b1 regulates follistatin mRNA expression during in vitro bovine granulosa cell differentiation. J Cell Physiol 207(1): 40-48.
- Novaro, V., Pustovrh, C., Colman-Lerner, A., Radisky, D., Lo Nostro, F., Paz, D., Jawerbaum, A. and Gonzalez, E. (2002). "Nitric oxide induces gelatinase A (matrix metalloproteinase 2) during rat embryo implantation." Fertility and Sterility 78(6): 1278-87.
- Chiappe, M. E., Lattanzi, M. L., Colman-Lerner, A. A., Baranao, J. L. and Saragueta, P. (2002). "Expression of 3 beta-hydroxysteroid dehydrogenase in early bovine embryo development." Molecular Reproduction and Development 61(2): 135-41.
- Novaro, V., Colman-Lerner, A., Ortega, F. V., Jawerbaum, A., Paz, D., Lo Nostro, F., Pustovrh, C., Gimeno, M. F. and Gonzalez, E. (2001). "Regulation of metalloproteinases by nitric oxide in human trophoblast cells in culture." Reprodroduction Fertility and Development 13(5-6): 411-20.
- Pomata, P. E., Colman-Lerner, A. A., Baranao, J. L. and Fiszman, M. L. (2000). "In vivo evidences of early neurosteroid synthesis in the developing rat central nervous system and placenta." Brain Research, Developmental Brain Research 120(1): 83-6.
- Pignataro, L., Lerner, A. A., Baranao, J. L. and de Plazas, S. F. (1998). "Biosynthesis of progesterone derived neurosteroids by developing avian CNS: in vitro effects on the GABAA receptor complex." International Journal of Developmental Neuroscience 16(5): 433-41.
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