These regions, found in DNA of human, mouse, and other mammals in hundreds of thousands of copies, are called retrotransposons because they have the ability to propagate and insert themselves into different positions within the genome. The research, published in the October issue of Developmental Cell, suggests that retrotransposons may not be just the "junk DNA" once thought, but rather appear to be a large repository of start sites for initiating gene expression. Therefore, more than one third of the mouse and human genomes, previously thought to be non-functional, may play some role in the regulation of gene expression and promotion of genetic diversity.

Dr. Barbara B. Knowles and colleagues from The Jackson Laboratory in Bar Harbor, Maine, found that distinct retrotransposon types are unexpectedly active in mouse eggs, and others are activated in early embryos. Surprisingly, by acting as alternative promoters, retrotransposon-derived controlling elements drive the coordinated expression of multiple mouse genes. "To our knowledge, this is the first report that such elements can initiate synchronous, developmentally regulated expression of multiple genes," says Dr. Knowles. "Also, random insertions of these elements can introduce variation in genes, potentially altering their function."

The researchers think that expression of retrotransposons during very early stages may contribute to the reprogramming of the mammalian embryonic genome, a prerequisite for normal development.

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Five transcriptional regulators guide future B cells along this pathway, activating genes that move the cell to the next stage and enabling the cell to respond to specific chemical signals later on. For example, the transcription factors PU.1 and lkaros are crucial early in the process, nudging a multi-potent progenitor cell -- stage 1, which could become any type of blood cell -- toward becoming a lymphoid progenitor, stage 2. They trigger the expression of certain receptors on the cell surface, such as Flk2 followed by IL-7R, which are necessary for receiving subsequent external signals.

In the next step, the gene for a regulatory protein known as E2A cooperates with PU.1 to activate another regulatory gene called EBF. EBF and E2A act together to push the lymphoid progenitor towards stage 3, a specified pro-B cell. At this stage, many of the genes expressed in B cells have been activated and the genes that encode antibodies have begun the process of recombination.

Finally, EBF and E2A activate a regulator called Pax-5, which pushes the specified pro-B cell to stage 4, a committed pro-B cell. After this point, there is no turning back.

"This is a complicated sequence of events," Singh notes. "There's no denying it." At each stage, different markers or receptors appear on the cell surface, which helps the researchers monitor a cell's progress and enables the cell to reach the next stage.

"To make real use of stem cells we will have to assemble genetic regulatory networks such as this for each cell type we want to generate," Singh added. "This is the next challenge facing the field. Molecular biologists are used to manipulating single genes, but this may require controlling several components in an ordered manner to properly direct a stem cell through a given developmental sequence."

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