The evolutionary history of the extracellular calcium-sensing receptor and its role in skeletal development
Herberger, Amanda L.
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As one of the most interesting members of the G protein-coupled receptor (GPCR) superfamily of proteins, the calcium-sensing receptor (CaSR) is restricted in its presence to the chordate-vertebrate lineage, pointing to an interesting possible link between the evolutionary emergence of CaSR and of vertebrate-type mineralized skeleton, and, more generally to the vertebrate system for calcium homeostasis. My thesis is framed in the context of CaSR evolution from an ancestral glutamate receptor-like GPCR, and of adaptive changes in the receptor related to habitat. By employing molecular phylogenetic, genomic, evolutionary developmental (evo-devo), and physiological approaches, I explored the core hypothesis that CaSRs evolved contemporaneously with the evolution of vertebrate mineralized-skeletal tissues. I explored the hypothesis that the CaSR subgroup of family C GPCRs evolved as a result of adaptive evolution. Tests for evolutionary selection among CaSRs, and some CaSR-like proteins, overall, revealed strong purifying selection, along with evidence for adaptive selection among major vertebrate clades, suggesting these episodes of positive selection may be linked to the natural history and physiology of calcium homeostatic patterns in aquatic and terrestrial vertebrate groups. I explored the hypothesis that CaSR is essential for proper developmental skeletal morphogenesis. Experimental studies addressed gaps in early vertebrate CaSR knowledge by exploring, in an evo-devo context, the essential role of CaSRs in vertebrate bone biology using the zebrafish model system. The experimental findings demonstrated a dependence on CaSR for normal skeletal development and subsequent morphogenesis, and point to an important involvement of CaSR in bone biology in piscine vertebrates. On a larger scale, my studies signal the probable importance of this receptor in skeletal emergence and development early in chordate-vertebrate evolution. In the course of the work, I also sequenced a cDNA for CaSR in the elephant fish. That sequence was used in the phylogenetic analyses. I also constructed three-dimensional homology models of CaSR receptor proteins that supported the phylogenetic analyses and the tests of selection.