Origins of Sexual Dimorphism in the Craniofacial Skeleton

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SUMMARY Phenotypic differences between males and females, termed sexual dimorphism, are a critical biological variable. Sex-based variation produces distinct biting kinematics, differential prevalence and severity of musculoskeletal conditions, and a variety of medical issues often requiring surgery. Despite these data indicating a clear impact of sex on craniofacial function and health, a critical gap in our knowledge includes the developmental stage at which males and females begin to differ in phenotype, including in common model organisms such as mice, chickens, and fishes. Further, we do not know the underlying mechanisms that generate variation in sexual dimorphism, such as the effects of genetic background and hormone signaling, particularly in early facial development. We model human sexual dimorphism using cichlid fishes, which have evolved exceptional craniofacial variation, enable easy manipulation of embryonic development through immersion of animals in chemicals, and mirror human sexual dimorphism in terms of effects on the mandible and variation due to genetic background. Given that the molecules that control facial development are highly conserved across vertebrates, this work may identify new mechanisms and genes that regulate musculoskeletal variation in humans. For example, Pdgfra regulates orofacial clefting in humans, mice, and fishes. The central question of this project is how sex generates functional variation in shape of the craniofacial skeleton. This Phase 2 application will focus on morphology, developmental time, and candidate genes to lay the foundations for future R01 applications focused on cellular and molecular mechanisms. In Aim 1, we will assess developmental origins of sexual dimorphism in bone shape and material properties between the sexes. We will also evaluate genetic risk factors that add further variation to sex-based phenotypes. These data will define when sex generates variation in the craniofacial skeleton and identify specific bones, timepoints, and candidate genes for a future R01 grant. In Aim 2, we will assess the morphological role of sex hormones in embryonic bone development. We predict that these hormones not only regulate bone patterning in both sexes, but variation in hormone signaling drives male-female differences and species-specific presentation of sexual dimorphism. Completion of this aim will extend our knowledge of hormones in adult bone biology to embryonic stages, which is currently a major gap in our understanding. We will also identify developmental windows and critical cell types for future mechanistic study in an R01 application. This project was conceptualized for an initial SC-TRIMH due to potential integration within this group and utilizes the Pre-clinical Assessment Core (PAC), Multiscale Computational Modeling (MCM) core, Advanced Fabrication & Testing (AFT) core, and the Administrative Core. It also synergizes with two other COBRES at Clemson University that support the Clemson University Genomics and Bioinformatics Facility which is important for Aim 1.2.