Project Summary
During development of the human brain, synaptic connections undergo intensive rewiring in order to form
mature circuits. Disruption of developmental remodeling in humans is linked to neurological disorders such as
schizophrenia and autism spectrum disorders. The goal of this project is to identify conserved mechanisms that
direct synapse remodeling. The ease of genetics, couple with the simpler organization and invariant
architecture of invertebrate nervous systems offer strong advantages for studies of neuronal remodeling. My
work focuses on the remodeling of GABAergic dorsal D-class (DD) motor neurons in the nemaode
Caenorhabditis elegans. Prior studies have largely focused on the remodeling of presynaptic terminals. In
contrast, my preliminary work has focused on understanding mechanisms that direct the elimination of
postsynaptic receptors during remodeling. post-synaptic domain. The Francis lab previously demonstrated that
the homeodomain transcription factor dve-1 is required for synapse elimination in GABA neurons. My work
focuses on two putative DVE-1 targets, the calcineurin-like EF-hand protein CHP1/chpf-1 and the regulatory
subunit of CalciNeurin PPP3R1/cnb-1, that were shown to be downregulated in dve-1 mutants. My preliminary
studies suggest that mutation of either cnb-1 or chpf-1 disrupt synapse elimination during remodeling. My
proposed work will determine the functional requirement and site of action for cnb-1, and identify the
contribution of calcineurin phosphatase and proteasomal function to synapse elimination (Aim 1). In Aim 2, I
will define how chpf-1 contributes to synapse elimination and maintenance. In Aim 3, I will identify additional
potential targets of dve-1 in the remodeling pathway by using neuron-specific RNA-seq. My proposed work will
advance our understanding of remodeling and the mechanisms of regulation, potentially providing targets for
future exploration.
