Abstract
Chromatin remodeling proteins of the chromodomain DNA-binding protein family, CHD7 and CHD8, mediate early neurodevelopmental events including neural migration and differentiation. As such, mutations in either protein can lead to neurodevelopmental disorders. How chromatin remodeling proteins influence the activity of mature synapses, however, is relatively unexplored. A critical feature of mature neurons is well-regulated endocytosis, which is vital for synaptic function to recycle membrane and synaptic proteins enabling the continued release of synaptic vesicles. Here we show that Kismet, the Drosophila homolog of CHD7 and CHD8, regulates endocytosis. Kismet positively influenced transcript levels and bound to dap160 and endophilin B transcription start sites and promoters in whole nervous systems and influenced the synaptic localization of Dynamin/Shibire. In addition, kismet mutants exhibit reduced VGLUT, a synaptic vesicle marker, at stimulated but not resting synapses and reduced levels of synaptic Rab11. Endocytosis is restored at kismet mutant synapses by pharmacologically inhibiting the function of histone deacetyltransferases (HDACs). These data suggest that HDAC activity may oppose Kismet to promote synaptic vesicle endocytosis. A deeper understanding of how CHD proteins regulate the function of mature neurons will help better understand neurodevelopmental disorders.
Highlights
Endocytosis and endosomal trafficking are required for the import of required nutrients and macromolecules as well as for cell growth, survival, and both autocrine and paracrine signaling[1]
We previously showed that chromatin reader, Kis, promotes neurotransmission and the apposition between presynaptic active zones and postsynaptic glutamate receptors at the Drosophila neuromuscular junction (NMJ)
We have previously shown that histone deacetylases (HDACs) and Kis act in opposition to influence synaptic function, synaptic morphology, and motor function at third instar NMJs
Summary
Endocytosis and endosomal trafficking are required for the import of required nutrients and macromolecules as well as for cell growth, survival, and both autocrine and paracrine signaling[1]. The vesicle sheds its clathrin coat and transitions to an early endosome, which can be trafficked to distinct cellular locations based on the fate of the cargo. Overgrowth and an excess of satellite synaptic connections, or boutons, have been reported in mutants of most endocytic genes at the Drosophila NMJ5,9–11 These supernumerary connections are thought to be due partially to the defect in membrane internalization of endocytic mutants and partially to defective signaling at the synapse that drives upstream signals for growth and development[9,10]. At the NMJ, decreased Kis leads to overgrowth of the presynaptic motor neuron, which is commonly observed in endocytic mutants, along with impaired neurotransmission and reduced postsynaptic glutamate receptors[15,16]. Whether Kis has different functions based on cell-type specificity remains to be answered
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