The origin of the parathyroid gland

Abstract

It has long been held that the parathyroid glands and parathyroid hormone evolved with the emergence of the tetrapods, reflecting a need for new controls on calcium homeostasis in terrestrial, rather than aquatic, environments. Developmentally, the parathyroid gland is derived from the pharyngeal pouch endoderm, and studies in mice have shown that its formation is under the control of a key regulatory gene, Gcm-2. We have used a phylogenetic analysis of Gcm-2 to probe the evolutionary origins of the parathyroid gland. We show that in chicks, as in mice, Gcm-2 is expressed in the pharyngeal pouches and the forming parathyroid gland. We find that Gcm-2 is present not only in tetrapods but also in teleosts and chondrichthyans, and that in these species, Gcm-2 is expressed within the pharyngeal pouches and internal gill buds that derive from them in zebrafish (Danio rerio), a teleost, and dogfish (Scyliorhinus canicula), a chondrichthyan. We further demonstrate that Gcm-2 is required for the formation of the internal gill buds in zebrafish. We also have identified parathyroid hormone 1͞2-encoding genes in fish and show that these genes are expressed by the gills. We further show that the gills express the calcium-sensing receptor, which is used in tetrapods to monitor serum calcium levels. These results indicate that the tetrapod parathyroid gland and the gills of fish are evolutionarily related structures, and that the parathyroid likely came into being as a result of the transformation of the gills during tetrapod evolution.pharyngeal endoderm ͉ vertebrate evolution ͉ Gcm-2 ͉ gills I n tetrapods, the parathyroid glands play a pivotal role in regulating extracellular calcium homeostasis, which is important to many physiological processes such as muscle contraction, blood coagulation, and synaptic activity. These glands detect changes in the levels of calcium in blood by means of the calcium-sensing receptor (CasR), which in turn modulates the secretion of parathyroid hormone (PTH), which acts to release calcium from internal stores such as bone and modulates renal ion transport (1). Developmentally, the parathyroid glands arise from the endodermal pharyngeal pouches; in humans and chickens, from the third and fourth pouches, and in mice, from the third pouch only. Importantly, studies in mice have demonstrated that the transcription factor encoded by Gcm-2 is a key regulator of parathyroid gland development. The expression of this gene is restricted to the parathyroid glands, and if this gene is mutated, the parathyroid glands fail to form (2-4).Fish, however, have been believed to lack parathyroid glands and PTH, and unlike tetrapods, the majority of calcium uptake in fish is from external sources. These differences are believed to reflect the fact that with the evolution of the tetrapods and the shift from an aquatic to a terrestrial environment, new controls for regulating calcium homeostasis had to be put in place, and thus the evolution of the parathyroid glands and PTH was a key event in facilitating this tra...

Expression of FoxC, FoxF, FoxL1, and FoxQ1 genes in the dogfish Scyliorhinus canicula defines ancient and derived roles for fox genes in vertebrate development

“…The later start to form at stage 24, presumably to increase the respiratory surface until the onset of pharyngeal respiration at stage 32 when they start to regress (Ballard et al, 1993). However, the function of the gill buds may not be restricted to respiration, and it has been shown that the gill buds of S. canicula are related to the parathyroid of tetrapods and are involved in regulating extracellular calcium levels (Okabe and Graham, 2004). FoxQ1 expression in B. floridae and C. intestinalis marks the endostyle, which is also derived from pharyngeal endoderm (Table 1 and references therein); however, the endostyle is not present in gnathostomes, where this structure is thought to have evolved into the thyroid (Ogasawara et al, 1999;Kluge et al, 2005).…”

Maintenance of Thymic Epithelial Phenotype Requires Extrinsic Signals in Mouse and Zebrafish

“…This is compatible with our observation of lack of Gcm2 expression in Foxn1-negative epithelia in thymic cysts. This has an evolutionary parallel in that the thymus evolves earlier than the parathyroid gland, which appears as a distinct anatomical structure only in tetrapods (19). The observation that Foxn1 expression does not resume after the silencing of the Noggin transgene (as a consequence of down-regulation of Foxn1) can be explained in at least two ways.…”

Characterization of a novel type I keratin gene and generation of transgenic lines with fluorescent reporter genes driven by its promoter/enhancer in Xenopus laevis

“…In particular, the GCM2 gene is involved in the formation of the parathyroid gland and gill in the mouse and zebrafish (Okabe and Graham, 2004). The zebrafish GCM2 gene is exclusively expressed in the pharyngeal ectoderm, and knockdown by morpholino antisense nucleotides causes failure of gill filament budding (Okabe and Graham, 2004;Hogan et al, 2004). Therefore, the GCM2 gene may play a role in the regulation of the FGK gene in the external and internal gills of X. laevis.…”

“…The cis-regulatory element between À563 bp and À476 bp in region IV contains two putative binding sites for the transcription factors GCM and NFATC. In particular, the GCM2 gene is involved in the formation of the parathyroid gland and gill in the mouse and zebrafish (Okabe and Graham, 2004). The zebrafish GCM2 gene is exclusively expressed in the pharyngeal ectoderm, and knockdown by morpholino antisense nucleotides causes failure of gill filament budding (Okabe and Graham, 2004;Hogan et al, 2004).…”