Meeting Abstract
Our long arm bones allow us to reach for objects that our short fingers grasp and manipulate with remarkable dexterity. Since skeletal proportion is integral to vertebrate animal form and function, the variety of limb proportions is also a striking aspect of species diversity. However, little is known of the molecular mechanisms that determine the different lengths of individual limb bones in any species. Here, we leverage the extreme hindlimb proportion of the bipedal jerboa (Jaculus jaculus) and its close evolutionary relationship to the laboratory mouse (Mus musculus) to identify genes that underlie differential skeletal growth. Although expression levels diverged throughout the genome over approximately 55 million years since the last common ancestor of the two species, differences at only 10% of orthologous genes are associated with the skeletal growth rate differences that contribute to limb proportion. These include genes that are expressed in multiple growth plates, which may be locally tuned by modular enhancers, and genes with more regionally restricted expression. Most of these genes had no known growth plate function, even though many are developmental transcription factors or are associated in other tissues with signaling networks that are critical regulators of skeletal elongation. We show that two of these, a retinoic acid antagonist and a BMP signaling inhibitor, are sufficient to modulate skeletal growth. Together, these findings suggest that the evolutionarily increased growth rate of the jerboa foot occurred in part by releasing growth potential that is restricted in mouse metatarsals.
