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Sex Determination Who's Who in Sex-Determination ResearchMost organisms come in one of two sexes. In mammals, instructions within the so-called sex chromosomes—the X and Y chromosomes—determine the fate of the fertilized egg. The sex determination process is set in motion in the embryo during the period that the gonads develop into either testes, ovaries, or, in organisms like the roundworm, an organ that is a combination of both. The carefully orchestrated process of sex determination involves interactions between different molecules within cells, as well as interactions between cells. When some of the steps involved in this intricate process go wrong, unusual sexual characteristics may develop. The degree to which particular genes are expressed is very important to the normal development and health of an organism. Organisms that determine sex via a pair of mismatched chromosomes have a special challenge. In the case of humans, females have twice the number of X chromosomes as males do, and the solution that has evolved is to turn off one of the female X chromosomes. Other animals have evolved different ways of achieving an equal balance in gene expression between the sexes—a process called dosage compensation. Several HHMI investigators are studying the genes on the sex chromosomes that lead to male or female development, the mechanisms responsible for the formation of the gonads, and the process of dosage compensation in different organisms, including flies, worms, and mammals. Brief descriptions of their work follow. Barbara J. Meyer, Ph.D. HHMI investigator, professor of genetics and development in the department of molecular and cell biology at the University of California, Berkeley, and adjunct professor in the department of biochemistry and biophysics at the University of California, San Francisco, School of Medicine. Dr. Meyer and her research group have done pioneering work to dissect the complex molecular pathway that controls sex development in the roundworm C. elegans. In the worm, embryos with one X chromosome will develop into males while those with two X chromosomes will turn into hermaphrodites (organisms that have sexual characteristics of both male and female). How does a developing worm know how many X chromosomes it has? Dr. Meyer and her colleagues discovered the genetic pathways responsible for counting the number of X chromosomes inside cells. Interestingly, the same genes also control dosage compensation, a regulatory process that must work smoothly for the worms to survive. Dr. Meyer's group has done important work leading to the understanding of dosage compensation mechanisms in C. elegans. Sites of interest: Dr. Meyer's home page: Biographical information about Dr. Meyer: http://mcb.berkeley.edu/faculty/GEN/meyerb.html A summary of Dr. Meyer's research from the HHMI website: David C. Page, M.D. HHMI investigator, member of the Whitehead Institute for Biomedical Research, and professor of biology at the Massachusetts Institute of Technology. Dr. Page and his research group have conducted groundbreaking work in understanding how genes on the mammalian sex chromosomes—X and Y—affect the development of germ cells into either sperm or eggs. By mapping and sequencing the Y chromosome, Dr. Page and his colleagues found a genetic mutation in humans that causes a failure to produce sperm—the most common cause of male infertility. In addition, comparisons of the Y chromosome's sequence with the X chromosome's are yielding insights into the evolutionary pathway the sex chromosomes have followed. Sites of interest: Dr. Page's home page: Biographical information about Dr. Page: http://www.whitehead.mit.edu/research/faculty/page.html A summary of Dr. Page's research from the HHMI website: Marisa S. Bartolomei, Ph.D. HHMI investigator and associate professor in the department of cell and developmental biology at the University of Pennsylvania School of Medicine. Using the mouse as the model system, Dr. Bartolomei and her research group are unraveling the molecular signals that lead to the inactivation of one of the two X chromosomes in each cell of a female embryo. In mice, as in humans, females have two X chromosomes and males have one X and one Y. In mammals, X inactivation is the dosage compensation mechanism used to silence one X chromosome and to achieve equivalent X-linked expression in the two sexes. Dr. Bartolomei's group recently identified a gene located on one of the autosomes (the chromosomes other than the sex chromosomes) that, when mutated, disrupts the process of X inactivation. Sites of interest: Dr. Bartolomei's home page: Biographical information about Dr. Bartolomei: A summary of Dr. Bartolomei's research from the HHMI website: Mitzi Kuroda, Ph.D. HHMI investigator and professor of cell biology and of molecular and human genetics at Baylor College of Medicine. Like embryos in mammals, fruit fly embryos with two X chromosomes develop into females, and embryos with an X and a Y chromosome develop into males. The process of dosage compensation, however, differs. In mammals it involves the inactivation of one of the two X chromosomes of females, but in the fruit fly Drosophila melanogaster it involves the development of mechanisms to increase the expression of genes on the X chromosome of males. Dr. Kuroda's group has been studying a complex of proteins and RNA, specific to male cells, that binds to the X chromosome along its length. The researchers have found that the complex binds to a few dozen scattered sequences along the X chromosome and then uses a mysterious spreading mechanism to reach different genes and regulate their expression. Sites of interest: Dr. Kuroda's home page: A summary of Dr. Kuroda's research from the HHMI website: Jeannie T. Lee, M.D., Ph.D. HHMI investigator and assistant professor of genetics at Harvard Medical School and assistant molecular biologist at Massachusetts General Hospital. Dr. Lee's laboratory is investigating the process of X inactivation in mammals. The researchers use a genetic approach that combines studies in whole mice with those in an embryonic stem cell model capable of recapitulating X inactivation in culture. In particular, her group is focusing on the role of the Xist gene—the master switch on the X chromosome that directs the counting of X chromosomes in cells, choosing which X chromosome is to be inactivated and initiating the silencing mechanism. Dr. Lee's group has found a novel element that works with Xist to bring about long-distance changes on the X chromosome. A summary of Dr. Lee's research from the HHMI website: Judith Kimble, Ph.D. HHMI investigator and Vilas Professor of Biochemistry, Molecular Biology, and Medical Genetics at the University of Wisconsin–Madison. Dr. Kimble and her research group use the roundworm C. elegans to dissect the genetic program that governs the development of organs from single cells. They have found 50 or so genes that guide the formation of the worm gonad—the organ that contains the germ cells. In particular, they identified one gene that is critical for determining the actual shape of the gonadal tissue in hermaphrodite and male worms. In addition, the Kimble laboratory has identified a protein that binds RNA and causes hermaphrodites to switch from producing sperm to producing eggs. Sites of interest: Dr. Kimble's home page: A summary of Dr. Kimble's research from the HHMI website: Iva S. Greenwald, Ph.D. HHMI investigator and professor of biochemistry and molecular biophysics at Columbia University College of Physicians and Surgeons. Dr. Greenwald and her research group use gonad cells from the roundworm C. elegans as a model system to study how interactions between cells contribute to determining the fate of each cell in a developing organism. Specifically, Dr. Greenwald's group has focused on two cells located on the developing hermaphrodite gonad. Each cell can follow one of two paths: become a mature cell that stops dividing or become a cell that continues to divide and gives rise to the cells that will make up the uterus. While each cell has an equal chance of choosing one path or the other, both cells never follow the same one. How do the cells determine the correct choice? Dr. Greenwald's research has identified specific signals that go back and forth between the two cells and allow each cell to know what the other one is doing. Sites of interest: Dr. Greenwald's home page: A summary of Dr. Greenwald's research from the HHMI website: |
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