Abstract
CHD7 and CHD8 are chromatin remodeling proteins that regulate several neurodevelopmental events. Mutations in these chromatin remodeling genes occur in neurodevelopmental disorders including CHARGE Syndrome and Autism Spectrum Disorders. Kismet (Kis) is the sole Drosophila homolog of CHD7 and CHD8. We investigated the possibility that Kis influences retrograde synaptic signaling given that Kis restricts the synaptic levels of several cell adhesion molecules and facilitates endocytosis. Our data indicate that Kis restricts synaptic pMad while facilitating the localization of pMad to presynaptic motor neuron nuclei. While the increase in pMad at kis mutant synapses may contribute to the loss of Endophilin B, it may not influence the mislocalization of glutamate receptors relative to active zones or the locomotor phenotypes observed in kis mutants. Kis may antagonize Polycomb Repressive Complex 2 (PRC2) signaling to restrict synaptic pMad. Kis, including its chromatin remodeling/ATPase activity, is required in presynaptic motor neurons for proper synaptic pMad levels. In contrast, an ATPase-deficient Kis can rescue synaptic pMad when expressed in all tissues. Similarly, expression of human CHD7 in all tissues of kis mutants rescues synaptic pMad. Our data suggest a model where Kis restricts synaptic pMad both by transcription-dependent and transcription-independent mechanisms. These data may aid in a better understanding of the importance of chromatin remodeling for synaptic structure and function and the molecular changes correlated with neurodevelopmental disorders.
