Science and Technology, a member of the Maximov lab and the first author of this study, noted the team become interested in class IIa histone deacetylases (HDACs), which include HDAC4, in part because they have been implicated in regulation of transcription of non-neuronal tissues. "Class IIa HDACs are also known to change their cellular localization in response to various signals," he said. "There were hints that, in neurons, the translocation of HDAC4 from the nucleus to cytoplasm may be triggered by synaptic activity. We found that mutant mice lacking excitatory transmitter release in the brain accumulate HDAC4 in neuronal nuclei. But what was really exciting was our discovery that nuclear HDAC4 represses a pool of genes involved in synaptic communication and memory formation."
Coincidentally, Maximov had been familiar with these same genes since his postdoctoral training with Tomas Sudhof, a neuroscientist whose pioneering work resulted in the identification of key elements of the transmitter release machinery. "It was truly astonishing when their names came up in our in vitro genome-wide mRNA profiling screens for neuronal HDAC4 targets," Maximov said.
A Link to a Rare Human Disease
To learn more about the function of HDAC4 in the brain, the team wanted to study its role in a mouse model. First, however, the scientists had to overcome a serious technical obstacleHDAC4 also appears to protect neurons from apoptosis (programmed cell death), so complete inactivation of this gene would lead to neurodegeneration. To solve this problem, the team generated mice carrying a mutant form of HDAC4 that could not be exported from the cell nucleus. This mutant repressed transcription independently of neuronal activity.
Another surprise came after the team had already initiated their experiments. Underscoring the team's findings, a human genetic study was published linking mutations in the human HDAC4 locus with a rare form of mentPage: 1 2 3 Related medicine news :1
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