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Cellular traffic backups implicated in skeletal malformations

A defective link in the intracellular protein "transit system" may lie at the heart of some craniofacial defects, new research in zebrafish suggests.

In the Sept. 17 online issue of Nature Genetics, Vanderbilt University Medical Center researchers report the identification of a mutation that causes severe skeletal deformities in zebrafish by shutting down a critical protein transport pathway.

The findings are surprising, said Ela Knapik, M.D., lead investigator on the study, because this pathway is thought to be so universal that a defect would prove fatal just hours after fertilization. But the mutant fish, named crusher, hatched and survived to nine days, albeit with striking skeletal abnormalities ?craniofacial defects, kinked fins and shortened body.

The pathway affected by the crusher mutation is key to transporting proteins outside of the cell. All proteins are made in the endoplasmic reticulum (ER), a labyrinthine compartment just outside the cell's nucleus. Proteins are then "packaged" into transport containers called vesicles, which traverse the gelatinous cytoplasm of the cell's interior. The vesicles eventually dock with the Golgi, a structure that resembles a pancake stack and is the last major "transit station" of the cell. In the Golgi, proteins are modified into their active, final form before being shipped out to the surface of the cell in another type of vesicle. Once they reach their destination, the proteins either empty out into the extracellular space or take up residence in the cell membrane.

"Protein transport and secretion is a fundamental function of every living cell, in every organism," said Knapik, associate professor of Medicine and Cell and Developmental Biology. Similar mutations in yeast and cultured cells were lethal from the start, suggesting that no multicellular animal would be able to survive such a defect.

But, the crusher mutation appears to only affect chondrocytes, the cells th
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Source:Vanderbilt University Medical Center


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