Quantification of gene expression patterns to reveal the origins of abnormal morphogenesis

Abstract

The earliest developmental origins of dysmorphologies are poorly understood in many congenital diseases. They often remain elusive because the first signs of genetic misregulation may initiate as subtle changes in gene expression, which can be obscured later in development due to secondary phenotypic effects. We here develop a method to trace back the origins of phenotypic abnormalities by accurately quantifying the 3D spatial distribution of gene expression domains in developing organs. By applying geometric morphometrics to 3D gene expression data obtained by Optical Projection Tomography, our approach is sensitive enough to find regulatory abnormalities never previously detected. We identified subtle but significant differences in gene expression of a downstream target of the Fgfr2 mutation associated with Apert syndrome. Challenging previous reports, we demonstrate that Apert syndrome mouse models can further our understanding of limb defects in the human condition. Our method can be applied to other organ systems and models to investigate the etiology of malformations.