The connections between cells in brain circuits that produce behavior can change throughout life, a phenomenon referred to as plasticity. One mechanism contributing to brain plasticity consists of different types of experiences turning genes that control the connections between brain cells on and off (epigenetics). This research examines one gene that controls the expression of other genes by making a specific protein called Kismet; the team's previous work has shown that Kismet regulates the activity of other genes that control how brain cells are wired together. By more fully understanding the specific ways that Kismet regulates brain plasticity, the investigators hope to better understand how different experiential factors (such as social interaction) and biological factors (such as aging) affect gene expression to form or alter connections in the brain. This type of information will also be important for better understanding natural and disease-related changes that occur in the brain throughout life. This award will also support the enhancement of directed research opportunities for undergraduate students by building upon an existing Classroom Undergraduate Research Experience (CURE). The CURE class addresses a critical problem that multiple universities face: accommodating the large number of undergraduate students who want to participate in undergraduate research but cannot due to limited faculty: student ratios. By further improving the provision of significant research experiences for large numbers of undergraduates in a classroom setting, this work will help educational institutions to better addresses important pedagogical concerns in science education and training.
A major question in neuroscience is how signaling cascades integrate experiential, environmental and/or internal cues to form long-lasting changes in gene expression required to form precise neural circuits. This award will address this question by examining the epigenetic mechanisms that link steroid hormone receptor gene expression to axon pruning in the developing brain. Axon pruning is critical for proper synapse elimination required to sculpt precise neural circuits. Defective pruning is associated with altered brain connectivity and behavior. A premier model of developmental axon pruning is the pruning that occurs in the developing mushroom body (MB) neurons in the fruit fly Drosophila melanogaster. This pruning requires precise control of the expression of the steroid hormone receptor Ecdysone Receptor (EcR) in MB neurons, which is a cell-autonomous, rate-limiting step in axon pruning. Disruption of EcR expression in Drosophila leads to unpruned axons. The investigators have shown that Kis binds cis regulatory elements of EcR, where Kis is required to activate EcR transcription by promoting H3K36 methylation and H4K16 acetylation. Further, they have shown that Kis protein levels are themselves controlled by the TGF-Beta signaling pathway, which is known to promote EcR levels and MB axon pruning. This award will determine how Kis links TGF-Beta signaling to control EcR transcription and MB pruning. It will also determine how Kis promotes epigenetic changes to control EcR transcription and MB pruning.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
