Professor Bernie Degnan, from UQ's School of Integrative Biology, together with PhD student Gemma Richards and colleagues from France, have traced the evolution of the nerve cell by looking for pre-cursors in, of all places, the marine sponge.
"Sponges have one of the most ancient lineages and don't have nerve cells," Professor Degnan said.
"So we are pretty confident it was after the sponges split from trunk of the tree of life and sponges went one way and animals developed from the other, that nerves started to form.
"What we found in sponges though were the building blocks for nerves, something we never expected to find."
Professor Degnan said the science involved came from the relatively new area of paleogenomics, which is the study of ancestral genomes to paint a more accurate picture of animal evolution.
"What we have done is try to find the molecular building blocks of nerves, or what may be called the nerve's ancestor the proto-neuron," he said.
"We found sets of these genes in sponges, when we really didn't expect it.
"But what was really cool is we took some of these genes and expressed them in frog and flies and the sponge gene became functional - the sponge gene directed the formation of nerves in these more complex animals.
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Genetically engineered mice with the Smurf1 gene removed no longer responded to TNF alpha because Smurf1 was not present to label Smad1 and Runx2 with the ubiquitin destruction tag. As expected, mice with increased TNF alpha had lesser bone mass than their counterparts, a result partially reversed in mice where Smurf1 had been removed.
Bolstering the importance of the current paper is the fact that TNF alpha promotes the destruction of some types of cancer cells. While toxic when administered systemically, it has found a niche in preventing the spread of skin cancer, where it can be injected directly into a tumor. Other drugs then became available that shut down the TNF signal by directly inhibiting the protein-eating proteosomes that receive the signal. There is an existing anti-myeloma drug on the market, bortezomib, which shuts down the proteosomes that Smurf1 partners with to destroy Smad 1 and Runx2.
Thus, Xing's team will be looking at the effect of bortezomib over the next year to see if shutting down proteosomes in bone cells does indeed increase bone mass in mice engineered to have high levels of TNF alpha. Bortezomib, is a general proteosome inhibitor, however, and does not specifically target Smurf 1, and future efforts will seek to identify Smurf1-specific drug candidates. In the meantime, the team is also seeking other groups of ligases that, like Smurf1, contribute to bone loss because experiments revealed that Smurf1 is not responsible for 100 percent of the bone loss under inflammatory conditions.
Along with Xing, the study was led by Ruolin Guo, Motozo Yamashita, Qian Zhang, Quan Zhou, Di Chen, David G. Reynolds, Hani Awad, Laura Yanoso, Lan Zhao, Edward Schwarz, Ying Zhang and Brendan Boyce within the Department of Pathology at University of Rochester. The article published today in hard copy was first published online on June 19, 2008.
"Our over-all hypothesis is that in inflammatory diseases like RA, the function of a group of enzymes like Smurf1 gets turned on to cause proteasome degradation of key regulator proteins leading to bone loss," Xing said. "The real, future solution will involve a treatment that specifically addresses each of these."
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