The origin of the parathyroid gland - PubMed (original) (raw)

The origin of the parathyroid gland

Masataka Okabe et al. Proc Natl Acad Sci U S A. 2004.

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 1/2-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.

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Figures

Fig. 1.

Fig. 1.

Expression of Gcm-2 in the parathyroid gland and the pharyngeal pouches in the chick. (A_–_D) Whole-mount in situ hybridization of chick E11 thyroid (T) and parathyroid (P) glands for the following probes: Gcm-2 (A), PTH (B), CasR (C), and TTF-1 (D). Gcm-2 can be seen to be expressed in two round masses, the parathyroid glands, which are adjacent to the thyroid, which expresses TTF-1. The parathyroid glands additionally express PTH and CasR. (E_–_I) Expression of Gcm-2 in chicken embryos, staged as described in ref. . In these micrographs, anterior is to the left and ventral is to the bottom. OV, otic vesicle; pp, pharyngeal pouch; II–IV, pharyngeal arches. Expression of Gcm-2 starts in the third pharyngeal pouch at stage 18 (E), and then, as development proceeds, expression is also evident in the fourth pharyngeal pouch and additionally weakly in the second pouch (F). At stage 24, expression in the third and fourth pouches is concentrated in a region dorsal of the pharyngeal pouches and is lost from the second pouch (G). In Vibratome sections of stage-22 embryos (H), it is clear that Gcm-2 expression is localized to the pharyngeal endoderm and that, by stage 24, the region of the pharyngeal endoderm expressing Gcm-2 has thickened and given rise to round masses that are the parathyroid gland rudiments of the third and fourth pouches (I).

Fig. 2.

Fig. 2.

Phylogenetic analysis of the distribution of Gcm-2 and its expression in teleost (zebrafish) and chondrichthyan (dogfish) species. (A) A phylogenetic tree of vertebrate Gcm genes based on

clustal

analysis. Dr, zebrafish (Danio rerio); Gg, chicken (Gallus gallus); Hs, human (Homo sapiens); Mm, mouse (Mus musculus); Nf, Australian lungfish (Neoceratodus forsteri); Om, rainbow trout (Oncorhynchus mykiss); Sc, dogfish (Scyliorhinus canicula); Xl, Xenopus (Xenopus laevis). Branch lengths are in units of number of amino acid substitutions per site. (B) Schematic depicting the conserved linkage between Gcm2 and Elovl2 in humans on chromosome 6p24.2, in chickens on chromosome 2 ctg20.4, and in zebrafish on chromosome 24 ctg25479.1. (C_–_F) Gcm-2 expression in zebrafish embryos. In these micrographs, anterior is to the left and ventral is to the bottom. Gcm-2 initiates expression in the second pharyngeal pouch in early 3-day-old larval fish (indicated by arrowhead in C). Subsequently, Gcm-2 is expressed sequentially in the more posterior pouches (D), and, by day 4, Gcm-2 is expressed in all of the pouches (E). It is also apparent by day 4 that Gcm-2 is expressed in the developing internal gill buds emerging from the pharyngeal pouches (F). (G and H) Gcm-2 expression in dogfish embryos. This gene is expressed in the internal gill buds protruding from the pharyngeal pouches in stage-27 dogfish embryos (17). The pharyngeal arches are numbered II–VI.

Fig. 3.

Fig. 3.

Gcm-2 is required for the elaboration of the internal gill buds from the pharyngeal pouches in zebrafish. Zebrafish embryos were injected at the one-cell stage with either control or antisense Gcm-2 MOs. The embryos were then analyzed at day 5 for the presence of internal gill buds. (A_–_C) Five-day-old zebrafish larva injected with control MO. (A) Nomarski view of the pharyngeal region of a day-5 embryo injected with the control MO. The internal gill buds protruding from the pharyngeal pouches are clearly evident (arrowheads). (B) Embryo injected with control MO hybridized for Gcm-2. _Gcm-2_-expressing internal gill buds can be clearly seen protruding from the pharyngeal pouches. (C) Embryo injected with control MO, showing normal pharyngeal pouch formation as judged by Pax-9a expression. Each pharyngeal pouch is indicated by an arrowhead. (D_–_F) Five-day-old zebrafish larva injected with Gcm-2 antisense MO. (D) Nomarski view of the pharyngeal region of a E5 embryo injected with the antisense Gcm-2 MO. There are no internal gill buds protruding from the pharyngeal pouches. (E) Embryo injected with the antisense Gcm-2 MO hybridized for Gcm-2. There are no _Gcm-2_-expressing internal gill buds protruding from the pharyngeal pouches. (F) Embryo injected with the antisense Gcm-2 MO, showing normal pharyngeal pouch formation as judged by Pax-9a expression. Each pharyngeal pouch is indicated by an arrowhead. EY, eye; YK, yolk. Anterior is to left and ventral is to the bottom.

Fig. 4.

Fig. 4.

PTH genes in zebrafish. (A) A phylogenetic tree of PTH and PTHrP genes in vertebrates. Dr, zebrafish (Danio rerio); Gg, chicken (Gallus gallus); Hs, human (Homo sapiens); Mm, mouse (Mus musculus); Sa, seabream (Sparus aurata); Tr, fugu (Takifugu rubripes). (B) Comparison of the partial peptide sequences of zebrafish PTH and amniote PTH. The N-terminal 34 aa of mature human PTH peptide are sufficient for the biological activity of PTH. This alignment includes the N-terminal amino acids (1–34) with 2 aa before the final proteolytic cleavage site. (C) Gills in adult zebrafish express both the PTH genes and CasR. PTH and CasR were amplified from adult brain and gills by RT-PCR. Arrowhead indicates cDNA product.

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