Protein Transport and Spinal Cord Development Linked to Each Other

A new link between protein transport and spinal cord development in mice has been discovered by American scientists.

Researchers from the Johns Hopkins University School of Medicine and a team from the University of California, Berkeley, conducted the study.

David Ginty, professor of neuroscience and Howard Hughes Medical Institute investigator, said: "What I love about this discovery is the total surprise - we never before would have linked defects in the protein-secretion machinery and neural tube closure."

Researchers initially wanted to find new genes that control proper wiring of the hundred billion neurons in the nervous system. For this, they randomly introduced mutations in mouse genes, bred the mice and analysed the offspring for defects in nervous system development.

One mouse embryo examined by graduate student Janna Merte had a spinal cord that had failed to close into a tube. Conditions like spina bifida are caused by the failure of the tail end of the spinal cord to close but these new mice had a more acute condition, where the entire spinal tube had failed to close.

Janna then identified the mutated gene in this mouse as Sec24b, a gene already known to play a part in the process where cells package newly made proteins that have to be delivered to the cell membrane or sent outside the cell.

But all genes known to control normal spinal tube closure are known to orient cells in a flat sheet, just like the pattern of the hair follicles in skin.

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Ginty said: "We didn't really know what to do with Sec24b at first."

His team them joined hands with Berkeley professor Randy Schekman, who discovered the Sec24 gene in yeast.

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Another gene, Vangl2, when mutated led to similar defects in spinal closure. Now the scientists tried to find if Vangl2 and Sec24b interact with each other. They first engineered mice to contain mutations in both genes and found that 68 percent of mice had spina bifida and more than half died within four weeks of taking birth. This was proof enough that the two genes interacted with each other.

Since both proteins take part in neural tube closure, the team thought that perhaps mutations in Sec24b might affect the packaging of Vangl2. Mixing cell components and Vangl2 in a test tube, the researchers added either Sec24b or other related proteins. It was seen that only tubes containing Sec24b were able to package Vangl2 whereas other related proteins could not.

It was also found that even slight changes in the Vangl2 protein prevented Sec24b from properly sorting Vangl2. In fact, Vangl2 was found bundled inside the cell.

According to Ginty, proper cell patterning is possibly established with very early stage cellular processes that control and manage protein production and transport.

And the high occurrence of spina bifida in mice with altered Sec24b and Vangl2 suggests that defects in Sec24b and perhaps other Sec genes could be the basis of human spinal cord defects.

"It will be interesting to see if that is in fact the case," added Ginty.

The study has appeared in the December 6 issue of Nature Cell Biology.

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