Genetic, hormonal, and mechanical influences on sexually dimorphic bone development

Sex dimorphism, phenotypic differences between males and females, is widespread in the musculoskeletal system.

Within the craniofacial skeleton, this variation can result in differential biting mechanics and common conditions that can require surgical correction.

For instance, temporomandibular joint dysfunction affects 35 million patients in the US, with 3 to 8 times more women than men affected.

The central hypothesis of this grant is that craniofacial variation between sexes results from interactions of sex-determining genes and developmental genes (Aim 1), the hormone environment (Aim 2), and mechanical forces (Aim 3).

To assess this, we will capitalize on the unparalleled natural craniofacial variation among the evolutionary radiation of non-model cichlid fishes.

Given that cichlid facial variation mimics human facial variation and the molecular control of facial development is conserved across vertebrates, this may yield novel insights into the regulation of sexual dimorphism in human faces.

In Aim 1, we will investigate the origins of sex-specific bone shape, density, and material properties using three cichlid species that show diverse adult morphologies. Notably, all three species demonstrate sexual dimorphism, but the patterns of dimorphism are species-specific.

We will use micro-CT scanning, histological analysis, and RNA-seq to assess the cellular and transcriptional drivers of variation in sexual dimorphism during development.

In Aim 2, we will alter the sex hormone environment and assess the resultant effects on morphology, the activity of chondrogenic and osteogenic processes, and gene expression.

This will clarify the role of hormones in early bone patterning, as well as potential mechanisms through which ubiquitous endocrine disrupting chemicals in the environment may produce variation in facial development.

Applying these hormones in closely-related cichlids (comparable to comparing different mouse strains), enables additional investigation of gene by environment (GxE) interactions.

In Aim 3, we will capitalize on the fact that cichlids forced to eat with alternate feeding strategies (biting versus suction feeding) have a plastic response and remodel their facial skeleton.

We will assess how remodeling is distinct between the sexes in terms of shapes produced and cellular activity, with potential implications for differential exercise-induced remodeling between males and females. In all, we will assess interactions of sex with developmental genes, hormones, and mechanical strain.

This work will provide insights on the cellular and molecular mechanisms that generate variation in bone shape and may influence prevalence or severity of musculoskeletal medical issues between sexes.