Thursday, January 2, 2025
1/2/2025
PROJECT SUMMARY/ABSTRACT The nervous system is sexually dimorphic: sex-specific behaviors are observed across species and disease risk for many neurological disorders, including autism and Alzheimer’s disease, differs between males and females. How sex-specific functions of the nervous system are established remains a fundamental question in neurobiology. Glia are ideal candidates for driving these sex-specific functions. They promote the formation and removal of neuronal connections, modulate neuronal activity, and most notably, exhibit sex differences in gene expression. However, due to technical challenges in studying glia in mammalian systems, it remains unclear how glial sex differences arise and how they affect neuronal function. I will overcome these challenges by using an innovative model of sexually dimorphic glia in the highly tractable nervous system of C. elegans. Specifically, I will investigate sex differences in a glial subtype called CEPso glia. We discovered that a transcriptional reporter for a putative secreted protein (GRL-18) is expressed exclusively in CEPso glia of sexually mature males. We determined that male-specific gene expression in CEPso glia is controlled cell-autonomously and requires conserved regulators of sexual development, including the timing genes lep-2/Makorin and lep-5 and the sex identity gene mab-3/DMRT. Interestingly, CEPso glia are intimately associated with male-specific CEM neurons that begin responding to pheromones in the external environment and mediating male mate-seeking behavior at sexual maturity. This leads to our hypothesis that sex differences in glia promote the activation of a sex-specific circuit at sexual maturity. In Aim 1, I will determine the molecular mechanisms that establish glial sex differences. First, I will use single-cell sequencing approaches to comprehensively identify sexually dimorphic gene expression in CEPso glia and other glia of the adult nervous system. Next, I will use classical genetic approaches and unbiased genetic screens to identify novel regulatory factors that act downstream of conserved timing and sex identity factors to initiate sex-specific changes in glia. The significance is to identify glial-specific regulators that control sexually dimorphic gene expression. In Aim 2, I will determine whether sex-specific glial gene expression contributes to sex-specific neuronal functions and behavior. To test this, I will assay aspects of CEM neuron maturation and adult male mate-seeking behavior in wild type and mutant animals with feminized glia or lacking male-specific genes, including grl-18. The significance will be to show how glia switch on sex-specific circuits and behaviors in the adult nervous system, which can help to explain the striking sex biases observed in many neurological disorders.
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