The diversity of sex-specific behaviors in adult organisms have been well-described, as have anatomical differences in the nervous systems of each sex. In addition to their relevance in healthy nervous system function, sexual dimorphisms are also evident in neurological diseases such as Alzheimer's, Huntington's, and PTSD. To understand the role of neural dimorphisms in these disease states, the field must first elucidate the genetic and developmental mechanisms by which these dimorphisms are established in healthy nervous systems. This proposal aims to combine the power of C. elegans genetics and the elucidated neural connectomes of both hermaphrodite and male animals with new transsynaptic labeling technologies to describe the genetic pathways regulating synaptic dimorphisms in sex-shared neurons. In testing the hypothesis that sex-specific behaviors are a reflection of sex differences in the neural connectome, and that these differences are genetically regulated, our lab has described both synaptic pre-patterning and synaptic pruning mechanisms that contribute to formation of synaptic dimorphisms in C. elegans, and has shown that cell-autonomous regulation by the sex determination pathway in both the pre and postsynaptic sides of a given connection determines sex of the synapse. This proposal will characterize the genetic mechanisms controlling the development of these synaptic dimorphisms in the PHA and PHB phasmid sensory neurons.
In aim 1, transsynaptic labeling will be used to not only validate the dimorphic connectivity for the PHA phasmid sensory neuron, which is currently based on electron micrographical data, but also describe the developmental dynamics by which synaptic dimorphisms are established, and how this is regulated cell-autonomously by the sex determination pathway.
In aim 2, the highly-conserved DM domain gene, dmd-4, will be investigated for a role in controlling synaptic pruning. dmd-4 is expressed dimorphically in both the PHA and PHB phasmid neurons at the adult stage, and this dimorphic expression is cell-autonomously downstream of the sex determination pathway.
In aim 3, forward genetic EMS screens will be utilized to identify mutants unable to prune juvenile sex-shared synapses into mature sex-specific synapses, in both a hermaphrodite-specific and male-specific synaptically- labeled strain. This will ultimately enable the description of a genetic pathway by which sex-shared neurons undergo synaptic pruning to generate sexually dimorphic adult neural circuits.
This proposal aims to understand the developmental dynamics by which sexually dimorphic synaptic connections are established in sex-shared neurons, and the genetic mechanisms regulating these dynamics. This will inform on the little-understood developmental processes that result in marked neural dimorphisms in adult organisms, a crucial goal in furthering understanding of human diseases such as Alzheimer's, Huntington's, and PTSD, which are known to have sexual dimorphisms both at the level of presentation and correlated gene expression patterns.
|Bayer, Emily A; Hobert, Oliver (2018) Past experience shapes sexually dimorphic neuronal wiring through monoaminergic signalling. Nature 561:117-121|
|Oren-Suissa, Meital; Bayer, Emily A; Hobert, Oliver (2016) Sex-specific pruning of neuronal synapses in Caenorhabditis elegans. Nature 533:206-11|