The packaging of nuclear DNA in chromatin is important for gene expression, DNA repair, and DNA replication. Although many chromatin remodeling proteins are implicated in development of the brain and nervous system, their roles at the synapse are relatively unexplored. We have found that Kismet (Kis), a chromatin remodeling protein, regulates the function and organization of the Drosophila neuromuscular junction, an excitatory synapse similar to mammalian central nervous system synapses. Kis is similar to the mammalian chromatin helicase binding domain (CHD) proteins CHD7 and CHD8, both of which are implicated in neurodevelopmental disorders including CHARGE Syndrome and autism spectrum disorders, respectively. The pathology of these disorders is correlated with misexpression of genes important for synaptic function. There is virtually no information, however, on how altering chromatin remodeling leads to synaptic dysfunction. The goal of this proposal is to better understand how the chromatin remodeling protein, Kis, regulates synapse organization and function. Mutations in kis lead to reduced neurotransmission and recycling of presynaptic vesicles, and increased levels of cell adhesion molecules at the synapse. We hypothesize that Kis promotes synaptic function and organization by regulating synaptic levels of cell adhesion molecules thereby affecting the recycling of synaptic vesicles. To test this hypothesis, we will first assess whether Kis is required for particular types of synaptic vesicle recycling. Then we will determine whether Kis directly regulates transcription of genes that encode cell adhesion molecules or proteins required for recycling of synaptic vesicles. Finally, we will determine whether the increased expression of cell adhesion molecules at the synapse of kis mutants is responsible for impaired synaptic vesicle recycling. These data will help us better understand how chromatin remodeling proteins enable synapse function and provide mechanistic insight into neurodevelopmental disorders.
This work will help us better understand how varying the expression of genes in brain cells leads to abnormal communication between neurons. Altered gene expression is a hallmark of neurodevelopmental disorders like intellectual disability and autism spectrum disorders. A better understanding of how altered gene expression affects communication between neurons could lead to the development of new treatments for these disorders.
