Decoding Sex Differences in the Brain, One Worm at a Time

Sex differences in the brain are prominent features across the animal kingdom. Understanding the anatomical and regulatory mechanisms behind these differences is critical for both explaining sexually dimorphic behaviors and developing sex-targeted treatments for neurological disorders. Clinical studies considering sex biases and basic research on animal models have provided much evidence for the existence of sex differences in the brain and, in a larger sense, sexual dimorphisms in the nervous system. However, due to the complexity of structure and dimorphic behaviors, it is yet unclear precisely how neuronal sexual dimorphisms are regulated on a molecular or cellular level. This commentary reviews available tools for investigating sexual dimorphisms using a simple model organism, the roundworm Caenorhabditis elegans (C. elegans), which enables one to study gene regulation at single-cell resolution with a number of cutting-edge molecular and genetic technologies. I highlight the doublesex/mab-3 family of transcription factors, first discovered in invertebrates, and their roles in a potentially universal regulatory mechanism underlying neuronal sexual dimorphisms. Studies of these transcription factors using C. elegans, fruit flies, and vertebrates will promote our understanding of fundamental mechanisms behind sex differences in the brain.