Really Old Hormones Up to New Tricks: Glycoprotein Hormone Subunits May Have Roles in Development

One of the great questions in the discipline of endocrinology is the evolutionary origin of the hormones and receptors at the foundation of endocrine regulation. The origin of the pituitary gland itself and its essential hormones has been debated for many decades (1, 2). For a long time, researchers at France’s Museum National d’Histoire Naturelle in Paris, i.e. M. M. Fontaine and Y. A. Fontaine and their students, have been interested in this very question. Now, continuing this tradition, Dos Santos et al. (3) deciphered the evolution of the glycoprotein hormones. Most of us know that LH and FSH control reproduction. These hormones are composed of a common glycoprotein α-subunit and a dissimilar β-subunit that confer the specific hormonal actions of these and other members of the family such as human chorionic gonadotropin and TSH. Querat (4) is well known for sorting out the messy phylogeny of the glycoprotein β-subunits, and he also previously helped to resolve the issue of the number of gonadotropins present in fish species. It is clearly established that the piscine gonadotropic hormones previously known as gonadotropin-I and -II (GTH-I and GTH-II) are indeed the fish equivalents of classical mammalian FSH and LH, respectively (4, 5).

More recently a putative hormone, thyrostimulin, was discovered by Hsueh and colleagues (6) and was so named because it activates TSH receptors and stimulates T₄ production. Other reports since then support this function. We could refer to thyrostimulin as one of the newest hormones; however, this would not be correct, given the results of Dos Santos et al. (3). Extensive invertebrate and vertebrate genome searches and rigorous phylogenetic analyses indicate that the glycoprotein subunits making up thyrostimulin have been around since the origins of the complex bilateral animal body plan more than 500 million years ago in the early Cambrian period. Thyrostimulin is presumably composed of the heterodimer of glycoprotein A2 (GPA2) and glycoprotein B5 (GPB5). It is these hormone-like subunits that Dos Santos et al. (3) set out to study with an eye on possible functions. They discovered differences in tissue distribution, GPA2 being more widely expressed in the amphioxus body than GPB5, with GPA2 expression levels being up to 100 times higher than those of GPB5. Often GPA2 and GPB5 are not even coexpressed. This raises the important question of whether GPA2 and GPB5 follow the general rule of the other glycoprotein hormones LH, FSH, and TSH that require α/β dimerization and glycosylation to be fully functional in vivo.

What are the possible functions of GPA2 and GPB5? Dos Santos et al. (3) used in situ hybridization and the amphioxus as the model system to explore developmental expression of GPA2 and GPB5 and their presumptive target, the glycoprotein-related receptor. Amphioxus is at the base of the vertebrate family tree and is a free-living invertebrate cephalochordate that has the main vertebrate characteristics as an adult. These animals are filter feeders and are also known as lancelets because of the sword-like body form. It should be noted that the ancestor of amphioxus, the famed Burgess Shale fossil, Pikaia gracilens, is dated at about 505 million yr old and resembles its modern-day cousin. There has been an interest in the endocrine systems of amphioxus since the 1960s. These curious animals have served science particularly well in studies of the evolution and developmental roles of HOX genes (7). In the embryonic amphioxus, expression of GPA2 was much more restricted than GPB5. One significant observation was the expression of GPA2 in the region of Hatshek’s pit. This structure forms as a dorsal evagination of cells from the mouth epithelium and has long been speculated to be a homolog of the vertebrate pituitary gland. This idea was strengthened by Gorbman’s observation of an infundibulum-like outgrowth along the right margin of the brain and notochord than makes contact with Hatchek’s pit (2). This system bears considerable resemblance to the vertebrate hypothalamo-adenohypophyseal system, perhaps most like that of the lamprey (1). It is possible that neurohormones could be delivered by diffusion to the cells in Hatchek’s pit expressing GPA2.

However, the main interest lies in the hypothesis that GPA2 and GPB5 are developmental regulators. Expression studies in amphioxus embryos indicate that they are not always expressed at the same place or developmental stage, suggesting that dimerization of the two glycoproteins does not always happen. Indeed, the expression of the receptor overlaps with or is in close proximity to GPA2, especially in the cerebral vesicle, club-shaped gland, and Hatchek’s pit. So GPA2 could work alone or dimerize with another as-yet-unidentified partner to activate the receptor. One key observation is that these glycoproteins also share considerable structural similarities with a bone morphogenic protein antagonist subfamily that has roles in embryonic development and tissue remodeling (8). Thus, it is possible that GPA2 and GPB5 regulate development through modulation of bone morphogenic protein, but this remains only a hypothesis. However, as the authors themselves discuss, there are documented important functions for the classical pituitary glycoprotein α-subunit in humans that we so often neglect. The free glycoprotein α-subunit can stimulate differentiation of prolactin cells in the pituitary (9) and endometrial stromal cell decidualization in the placenta (10, 11). Moreover, it has been suggested that the hyperglycosylated free human chorionic gonadotropin-β subunit in humans promotes cell growth and malignancy by blocking apoptosis through antagonizing the TGFβ receptor (12). The hypothesis that GPA2 and GPB5 are developmentally important hormones in amphioxus, other protochordates, or true vertebrates is not only reasonable but also wholly testable. We can all look forward to the expansion of the functions of GPA2 and GPB5 from recent partners in a TSH-like hormone to ancient regulators of animal development.

Disclosure Summary: The author has nothing to disclose.

For article see page 3815

Abbreviations

 
• GPA2,

  Glycoprotein A2;

 
• GPB5,

  glycoprotein B5.