Using comparisons between species and anatomical locations to discover mechanisms of growth plate patterning and differential growth

Introduction Despite our shared ancestry, humans and other primates show great diversity in skeletal form. The functional significance of this variation has been well-studied, and our understanding of it continues to be refined. While obviously important for determining the selective pressures that have shaped the skeleton throughout evolutionary history, functional explanations alone do not tell the complete evolutionary story. Each individual is the result of a developmental process that interprets its particular genotype into a functional phenotype. Therefore, to fully appreciate the evolutionary process we must also uncover the genomic and developmental mechanisms that generate the phenotypic variation upon which selection can act (Hendrikse et al., 2007; Rolian, 2008; Reno, 2014, 2016). The vertebrate postcranial skeleton initially forms as cartilage models during early embryological patterning that are subsequently replaced by bone, a process called endochondral ossification (Long and Ornitz, 2013; also see Chapter 7 for additional review of endochondral ossification). During ontogeny, growth plates preserve regions of cartilage that permit rapid longitudinal growth. The differential growth performance of the individual growth plates gives the skeleton its eventual shape (Wolpert, 1981). This process is commonly studied as two distinct stages. First, skeletal patterning is understood to be guided by developmental control genes that establish body axes, define developmental fields, assign positional information, and direct the aggregation, proliferation, and differentiation of mesenchymal cells (Johnson and Tabin, 1997). Second, differential growth is viewed as the result of cellular organization behaviors and intercellular signaling networks within the growth plate and the surrounding perichondrium (Maes and Kronenberg, 2012). Recent efforts have begun to identify how key developmental patterning genes, including Hox, can specify growth behaviors in the long and short bones of the limbs (Villavicencio-Lorini et al., 2010; Kuss et al., 2014). This knowledge is an important step toward understanding processes by which species-specific morphologies, including limb and digit lengths, have evolved. Three types of biological variation have been used to discover the links between early skeletal patterning and differential growth. First, dramatic changes can be produced through genetic manipulation and gene targeting (Capecchi, 1994). This is the most utilized of the three sources, and the strength of such models is that particular phenotypes and their developmental basis can be ascribed to the action of individual genes. Second, the discovery of the deep conservation of developmental control genes and gene regulatory networks has reinvigorated comparative developmental analyses (Carroll, 2008).