More About MIX-1
Development from a single cell to a mature multicellular organism requires careful regulation of proteins so that they are present in the right place and time. For example, a host of proteins controls mitosis, in which a cell divides to yield two cells with the same chromosomal complement as the parent cell. The animation emphasizes the role of the MIX-1 protein, which is essential for two distinct aspects of cellular function in Caenorhabditis elegans.
During most of the cell cycle, the chromosomes are uncoiled and spread throughout the nucleus. In preparation for mitosis, the chromosomes condense, and they can be seen with a light microscope. In organisms as diverse as yeast, C. elegans, and humans, a related group of proteins forms a complex that regulates chromosome condensation. The complex includes MIX-1 and its partner SMC-4.
MIX-1 also plays a role in dosage compensation. For many genes, the number of active copies of a gene is very important. Too much or too little gene expression can be fatal. For organisms in which sex is determined by a distinct set of sex chromosomes, the male and the female have different chromosomal complements. In C. elegans, the hermaphrodite has two X's (XX) and the male has one X (XO), and dosage compensation is achieved by turning down the expression of both hermaphrodite X chromosomes. During evolution, MIX-1 was apparently recruited to be involved in dosage compensation. Different partner proteins help MIX-1 function in both chromosome condensation and dosage compensation.
For dosage compensation, a complex of proteins that includes MIX-1 binds specifically to the X chromosomes to turn down transcription from both X's. The timing of the production of key members of the protein complex is highly regulated in C. elegans hermaphrodites. For example, just before X-chromosome transcription begins in the early hermaphrodite embryo, SDC-2 is produced in a burst of synthesis. SDC-2 is not produced in males. SDC-2 targets MIX-1/DPY-27 to the complex forming on the X chromosomes.
MIX: Mitosis, X Chromosome
SMC: Structural Maintenance of Chromosomes
SDC: Sex Determination and Dosage Compensation
How can one cell use the same protein for different functions? The protein could be produced only at very specific times in the cell cycle, serving different functions at each time. Another posscomplex with other molecules, the protein can do more than just one thing in a cell. These partnerships can also ensure that a protein is active only at particular times or places.
This animation shows how MIX-1 facilitates both chromosome condensation and dosage compensation. Two cycles of mitosis are shown. The first cycle illustrates the role of MIX-1/SMC-4 in condensing chromosomes; the second cycle shows how MIX-1 partners with DPY-27/SDC-2 to cut X-chromosome transcription in half.
Part 1: MIX-1 and its partner SMC-4: Chromosome condensation
As the embryo develops, the timing of the production of regulatory proteins is carefully controlled. Note the rapid increase in the synthesis of MIX-1 and its partner SMC-4. The MIX-1/SMC-4 complex binds to all the dispersed chromatin, resulting in the formation of compact chromosomes that are essential for mitosis to proceed normally. Observe that MIX-1 also partners with another protein, DPY-27, to function in dosage compensation. This complex requires several other proteins, including SDC-2, to function. However, SDC-2 is not present before the onset of dosage compensation.
Part 2: MIX-1 partners with DPY-27 and SDC-2: Dosage compensation
At approximately the 40-cell stage of hermaphrodite development, a brief burst of SDC-2 synthesis occurs after replication but before the chromatin condenses. SDC-2 forms a complex with MIX-1 and DPY-27 that is found only on the X chromosomes. The complex regulates transcription from the two X chromosomes such that total transcription from two hermaphrodite X chromosomes is equivalent to that of one male X chromosome. Thus, the hermaphrodite compensates for having two doses of the X chromosome.
Different organisms have evolved many mechanisms by which the amount of X-linked gene expression is made equivalent in both males and females. Unlike C. elegans, in which gene expression from each of the two hermaphrodite X's is halved, in Drosophila, X-linked gene expression in the male, which has one X, is doubled. A third dosage compensation mechanism is used in mammals: one X chromosome in females is randomly inactivated, resulting in gene expression from only one of the two female X chromosomes. In each case, the end result is the same: the amount of X-linked gene products in the single-X male is equal to the amount in XX members of the opposite sex.
Proteins can interact with other proteins in many ways. MIX-1 and its partners group together, forming a “complex” of proteins in which each protein depends on other members of the complex to carry out specific biochemical functions. Different members of the complex have different roles. The function of individual members of the complex can be analyzed by mutating or chemically blocking one protein and examining how the function of the complex as a whole is affected. Researchers also learn about an individual protein's roles by comparing its function and structure in different species.
During most of the cell cycle, the cellís chromosomes are long thin strings dispersed throughout the nucleus. However, before lining up on the metaphase plate, the chromosomes condense into discrete units. Spindle fibers attach to the chromosomes, making equal segregation of the chromosomes between two daughter cells possible.
Mitosis is the process of cell division that results in two daughter cells with the identical genetic complement as the parent cell. During interphase, chromosomes are diffusely spread out in the cell nucleus. In this configuration, the DNA can replicate. Interphase typically is the longest phase of the cell cycle, lasting roughly 15 hours in a cell cycle of 16 hours. Only in the 1 hour of mitosis are chromosomes condensed into discrete bundles. However, this configuration is essential for proper segregation of the chromosomes into the daughter cells.
"Sex and Death in the Nematode Caenorhabditis elegans"
Describes the research of Dr. Barbara Meyer, including information on MIX-1 and its partners.
Meyer, B.J. 2000. Sex in the worm: counting and compensating X-chromosome dose. Trends in Genetics 16(6): 247–53.
Dawes, H.E., Berlin, D.S., Lapidus, D.M., Nusbaum, C., Davis, T.L., and Meyer, B.J. 1999. Dosage compensation proteins targeted to X chromosomes by a determinant of hermaphrodite fate. Science 284(5421): 1800–4.
Hagstrom, K.A., Holmes, V.F., Cozzarelli, N.R., and Meyer, B.J. 2002. C. elegans condensin promotes mitotic chromosome architecture, centromere organization, and sister chromatid segregation during mitosis and meiosis. Genes & Development 16(6): 729–42.
Lieb, J.D., Albrecht, M.R., Chuang, P.T., and Meyer, B.J. 1998. MIX-1: an essential component of the C. elegans mitotic machinery executes X chromosome dosage compensation. Cell 92(2): 265–77.
Director: Dennis Liu, Ph.D.
Scientific Direction: Barbara Meyer, Ph.D.
Scientific Content: Donna Messersmith, Ph.D.
Animators: Chris Vargas, Eric Keller