The relationship between variable SHH signaling and the severity of structural defects in the face and brain

Embryonic shape plays an important role in the etiology of craniofacial birth defects, yet how morphological variation is generated early in development and contributes to disease incidence is poorly understood. Here we propose a model in which there is a predictable relationship between variation in Shh signaling, the underlying cellular and molecular processes that control growth, embryonic craniofacial shape, and the severity of facial defects. To test these predictions, we induced variation in Shh signaling in chick embryos using a neutralizing antibody (5E1), imaged embryos with µCT, and calculated the relationship of craniofacial shape to dosage. Our preliminary results demonstrate a continuous range of phenotypes, with a fully penetrant phenotype at the highest dose of cells and progressively more variable and less severe phenotypes at lower doses. These results confirm that the Shh pathway acts in a predictable manner on the incidence and severity of craniofacial dysmorphology, particularly in the brain and face. Ongoing analyses are focused on linking these results explicitly to variation in gene expression and cell proliferation. Ultimately, understanding how genetic and developmental mechanisms interact to generate phenotypic variation, from healthy to diseased, will enable both the prediction of facial malformations in utero and corrective genetic therapies in human embryos.