Inelegant Worms Provide New Clues About Gene Required for Development (7/4/2008)

The normal nematodes in Fern Finger's lab move in beautiful S-shaped curves across their Petri dish. In fact, it was these elegant movements that gave the tiny, clear worms the Latin name Caenorhabditis elegans. But the dish also contains worms with a very specific genetic defect, a mutant unc-85 gene, which are easily identified as the clumsiest dancers on the tiny dance floor.

The mutant worms, which are unable to move backward or even mate with one another despite valiant efforts, hold valuable information in their genetic makeup that could help scientists better understand the role of specific genes in both normal and abnormal development. While studying unc-85, Finger, a professor of biology at Rensselaer Polytechnic Institute, discovered that the gene significantly impacted DNA replication in the nervous system.

The findings appear in the July 1, 2008 edition of the journal Developmental Biology.

To make the discovery, Finger and her doctoral student Iwen Grigsby used a new variation of a specialized mapping technique to identify the genetic variation between the normal and mutant unc-85 genes. Finger found that the unc-85 gene encodes what is known as a histone chaperone protein - a protein that is essential for the packaging of DNA and the expression of different genes.

When worms were raised with a mutant unc-85 gene, the creation of new DNA strands is impaired during the last stages of development known the post-embryonic stage. Specifically, DNA replication in cells that produce neurons is blocked, creating the ungainly worms. Surprisingly, despite the presence of the genetic mutation, the worms still live to adulthood and are able to reproduce because they are hermaphrodites and can impregnate themselves.

To understand the role of unc-85 in the worms, the researchers used a confocal microscope to measure the amount of DNA in the neurons. They found that the replication of DNA was affected in the unc-85 mutants.

To pinpoint what part of the body the mutant gene most directly impacts, worms were then developed that expressed unc-85 fused to a protein that glows under the microscope wherever it is genetically expressed in the worm.

Under the microscope, unc-85 was found throughout nearly every cell nucleus in the worm during the earliest stages of development, but as development progressed, the protein became restricted to cells that replicate DNA, primarily in the neuronal precursors and reproductive organs.

"Since unc-85 is so widely expressed in the organism at the start of the development, the limited extent of the mutant worms' outer symptoms are very surprising," Finger said.

Upon additional study, the researchers found that the gene encodes one of the two worm histone chaperone proteins known as Asf1. These genes are found in all fungi, plants and animals, including humans. Histone chaperones attach histones onto DNA and remove them from DNA. Histones are very small proteins that form into groups, making a sort of spool for a DNA strand to wrap around. The DNA/histone bundle is known as chromatin. This condensing of the DNA strand allows a massive strand of DNA to squeeze into a cell nucleus as it prepares for division and thus the sharing of the DNA. In addition, how tightly a gene sequence is spooled onto the DNA affects whether the DNA can be copied, which is important for duplicating the chromosome for cell division, and also for production of the protein encoded by the gene.

In the case of unc-85, the lack of this histone chaperones blocks DNA replication in cells that divide to produce neurons late in the development process. Finger is now looking to expand the research to better understand why and how the organism continues to undergo a certain level of normal cell division despite the genetic defect.

Note: This story has been adapted from a news release issued by Rensselaer Polytechnic Institute

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