Endocrine - Parathyroid Development

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Introduction

Embryonic origins of the endocrine organs of the neck

The parathyroid gland appears in the adult as a pair of inferior and a pair of superior "bumps" on the beside the (dorsal) thyroid (hence the name, "para"). The embryonic origin of this gland is from the endoderm of the third and fourth pharyngeal pouches, and could also have ectoderm and neural crest contributions. This developmental process also generates multiple small parathyroid clusters in addition to the main parathyroid glands.[1]


At 6 weeks a diverticulum elongates from the pouch, initially hollow and then solidifynig with cell proliferation.

Interestingly, the inferior parathyroid originates from the third pharyngeal pouch and the superior arises from the fourth pharyngeal pouch, the adult anatomical position is the opposite of the pharyngeal rostro-caudal order. This occurs due to the third pharyngeal pouch also giving rise to the thymus, the superior pair descend along with the thymus.

Parathyroid hormone (PTH) regulates calcium and phosphate levels in conjunction with parafollicular cells of the thyroid gland (calcitonin) and Vitamin D (dietary or synthesized in the skin).


The fetal parathyroids appear functional as they respond to calcium levels. The fetal calcium levels also higher than maternal levels.


Endocrine Links: Introduction | BGD Lecture | Science Lecture | Lecture Movie | pineal | hypothalamus‎ | pituitary | thyroid | parathyroid | thymus | pancreas | adrenal | gonad‎ | endocrine placenta | other tissues | Stage 22 | endocrine abnormalities | Hormones | Category:Endocrine
Historic Embryology - Endocrine  
1903 Islets of Langerhans | 1904 interstitial Cells | 1908 Pancreas Different Species | 1908 Pituitary | 1908 Pituitary histology | 1911 Rathke's pouch | 1912 Suprarenal Bodies | 1914 Suprarenal Organs | 1915 Pharynx | 1916 Thyroid | 1918 Rabbit Hypophysis | 1920 Adrenal | 1935 Mammalian Hypophysis | 1926 Human Hypophysis | 1927 Hypophyseal fossa | 1932 Pineal Gland and Cysts | 1935 Hypophysis | 1937 Pineal | 1938 Parathyroid | 1940 Adrenal | 1941 Thyroid | 1950 Thyroid Parathyroid Thymus | 1957 Adrenal

Historically, see also the 1938 paper on the fate of the ultimobranchial body within the human thyroid gland.[2]

Some Recent Findings

Human Embryo (week 6 - 8)[1]
  • Multiple roles for HOXA3 in regulating thymus and parathyroid differentiation and morphogenesis in mouse[3] "Previous studies have shown that the Hoxa3 null mutant lacks third pharyngeal pouch derivatives, the thymus and parathyroids by E18.5, and organ-specific markers are absent or downregulated during initial organogenesis. Our current analysis of the Hoxa3 null mutant shows that organ-specific domains did undergo initial patterning, but the location and timing of key regional markers within the pouch, including Tbx1, Bmp4 and Fgf8, were altered. Expression of the parathyroid marker Gcm2 was initiated but was quickly downregulated and differentiation failed; by contrast, thymus markers were delayed but achieved normal levels, concurrent with complete loss through apoptosis. To determine the cell type-specific roles of Hoxa3 in third pharyngeal pouch development, we analyzed tissue-specific mutants using endoderm and/or neural crest cell (NCC)-specific Cre drivers. Simultaneous deletion with both drivers resulted in athymia at E18.5, similar to the null. By contrast, the individual tissue-specific Hoxa3 deletions resulted in small, ectopic thymi, although each had a unique phenotype. Hoxa3 was primarily required in NCCs for morphogenesis. In endoderm, Hoxa3 temporally regulated initiation of the thymus program and was required in a cell-autonomous manner for parathyroid differentiation. Furthermore, Hoxa3 was required for survival of third pharyngeal pouch-derived organs, but expression in either tissue was sufficient for this function." Developmental Signals - Homeobox
  • Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions[1] "In mammals, parathyroid hormone (PTH) is a key regulator of extracellular calcium and inorganic phosphorus homeostasis. Although the parathyroid glands were thought to be the only source of PTH, extra-parathyroid PTH production in the thymus, which shares a common origin with parathyroids during organogenesis, has been proposed to provide an auxiliary source of PTH, resulting in a higher than expected survival rate for aparathyroid Gcm2⁻/⁻ mutants. However, the developmental ontogeny and cellular identity of these "thymic" PTH-expressing cells is unknown. ...Our data show conclusively that the thymus does not serve as an auxiliary source of either serum PTH or parathyroid function. We further show that the normal process of parathyroid organogenesis in both mice and humans leads to the generation of multiple small parathyroid clusters in addition to the main parathyroid glands, that are the likely source of physiologically relevant "thymic PTH."" Endocrine - Thymus Development
More recent papers  
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
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Search term: Parathyroid Embryology

Ying Zhang, Guangpei Chen, Zhen Gu, Haijian Sun, Andrew Karaplis, David Goltzman, Dengshun Miao DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide. Int. J. Biol. Sci.: 2018, 14(5);508-517 PubMed 29805302

Funda Göker, Selim Ersanlı, Volkan Arısan, Erdal Cevher, Emine Elif Güzel, Halim İşsever, Beyhan Ömer, Gülay Durmuş Altun, Deniz Morina, Tuğba Ekiz Yılmaz, Elmire Dervişoğlu, Massimo Del Fabbro Combined effect of Parathyroid hormone and Strontium ranelate on bone healing in ovariectomized rats. Oral Dis: 2018; PubMed 29774969

Minghao Wang, Lingmi Hou, Maoshan Chen, Lin Ren, Peng Tang, Yi Zhang, Jun Jiang Thyroid hemiagenesis and Hashimoto's thyroditis-diagnostic and treatment pitfalls. World J Surg Oncol: 2017, 15(1);182 PubMed 28985747

Naoki Morito, Keigyou Yoh, Toshiaki Usui, Hisashi Oishi, Masami Ojima, Akiko Fujita, Ryusuke Koshida, Hossam H Shawki, Michito Hamada, Masafumi Muratani, Kunihiro Yamagata, Satoru Takahashi Transcription factor MafB may play an important role in secondary hyperparathyroidism. Kidney Int.: 2017; PubMed 28964572

Barbara Gellén, Dóra Zelena, Ted B Usdin, Árpád Dobolyi The parathyroid hormone 2 receptor participates in physiological and behavioral alterations of mother mice. Physiol. Behav.: 2017; PubMed 28890271

Development Overview

Parathyroid primordia (week 6 GA)[1]
Adult parathyroid anatomy
  • Endoderm - third and fourth pharyngeal pouches, could also have ectoderm and neural crest
  • 3rd Pharyngeal Pouch - inferior parathyroid, initially descends with thymus
  • 4th Pharyngeal Pouch - superior parathyroid
  • Week 6 - diverticulum elongate, hollow then solid, dorsal cell proliferation
  • Fetal parathyroids - respond to calcium levels, fetal calcium levels higher than maternal

Parathyroid Hormone

(PTH, parathormone or parathyrin) A polypeptide (84 amino acids) hormone which increases the concentration of calcium ions in the blood. Its actions oppose the hormone calcitonin from the parafollicular cells (C cells) of the thyroid gland, which decrease calcium. Acts through the parathyroid hormone receptor in bone, kidney and gastrointestinal tract.

  • stimulate osteoclasts - degrade bone matrix, releasing calcium
  • increase calcium gastrointestinal tract absorption

Parathyroid Hormone-related Protein

(PTHrP) Originally identified in the clinical syndrome humoral hypercalcemia of malignancy. It's developmental role is that of a regulatory protein expressed during the formation of many organs.

  • mammary gland development - epithelial-mesenchymal interactions[4]
  • chondrocyte differentiation[5]

Abnormalities

Hyperparathyroidism

Postnatal

  • Postnatal adult ageing increased parathyroid hormone plasma levels are associated with cognitive decline and dementia.
  • Parathyroid carcinoma (cancer) is a rare malignancy, occurring with an incidence of 0.5 to 4% of all cases of primary hyperparathyroidism.

Adult Histology


References

  1. 1.0 1.1 1.2 1.3 Liu Z, Farley A, Chen L, Kirby BJ, Kovacs CS, Blackburn CC & Manley NR. (2010). Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions. PLoS Genet. , 6, e1001251. PMID: 21203493 DOI.
  2. Kingsbury BF. On the fate of the ultimobranchial body within the human thyroid gland. (1935) Anat. Rec. 61(2): 155–173.
  3. Chojnowski JL, Masuda K, Trau HA, Thomas K, Capecchi M & Manley NR. (2014). Multiple roles for HOXA3 in regulating thymus and parathyroid differentiation and morphogenesis in mouse. Development , 141, 3697-708. PMID: 25249461 DOI.
  4. Dunbar ME & Wysolmerski JJ. (1999). Parathyroid hormone-related protein: a developmental regulatory molecule necessary for mammary gland development. J Mammary Gland Biol Neoplasia , 4, 21-34. PMID: 10219904
  5. Alman BA & Wunder JS. (2008). Parathyroid hormone-related protein regulates glioma-associated oncogene transcriptional activation: lessons learned from bone development and cartilage neoplasia. Ann. N. Y. Acad. Sci. , 1144, 36-41. PMID: 19076361 DOI.


Reviews

Zajac JD & Danks JA. (2008). The development of the parathyroid gland: from fish to human. Curr. Opin. Nephrol. Hypertens. , 17, 353-6. PMID: 18660669 DOI.

Parvari R, Diaz GA & Hershkovitz E. (2007). Parathyroid development and the role of tubulin chaperone E. Horm. Res. , 67, 12-21. PMID: 17008776 DOI.

Jüppner H. (2000). Role of parathyroid hormone-related peptide and Indian hedgehog in skeletal development. Pediatr. Nephrol. , 14, 606-11. PMID: 10912527

Articles

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Additional Images

Terms

  • parathyroid hormone - (PTH, parathormone or parathyrin) A polypeptide (84 amino acids) hormone secreted by the parathyroid gland, which increases the concentration of calcium ions in the blood. Its actions oppose the hormone calcitonin from the thyroid gland parafollicular cells (C cells), which decrease calcium. Acts through the parathyroid hormone receptor located mainly in bone, kidney and gastrointestinal tract. Hormone dual role is to: stimulate osteoclasts in bone to degrade bone matrix releasing calcium; increase gastrointestinal tract absorption of calcium.
Endocrine Terms (expand to view) 
  • adenohypophysis - (anterior pituitary, pars distalis) anterior part of pituitary embryonic development from surface ectoderm adenohypophyseal placode. Placode folds inward on the roof of the pharynx forming a transient structure Rathke's pouch.
  • adrenocorticotropin - (ACTH or corticotropin) anterior pituitary, peptide hormone stimulates the adrenal cortex to produce corticosteroid hormones — primarily cortisol — as well as small amounts of female and male sex hormones.
  • androstenedione - hormone precursor of testosterone and other steroidal androgens.
  • atrial natriuretic peptide - (ANP) heart, peptide hormone regulates blood pressure. A study suggests that its activating enzyme corin, and ANP together, have a role in placentation, by promoting trophoblast invasion and spiral artery remodelling. (PMID 22437503)
  • basophil cell - pituitary named by histological staining (deep blue, purple) different types produce different hormones: corticotrophs (ACTH, CRH), gonadotrophs (FSH, LH, GnRH), and thyrotrophs (TSH, TRH). See acidophil and chromophore cells.
  • C cells - parafollicular cells of the thyroid.
  • calcitonin - (CT) C cells of thyroid, peptide hormone thyroid
  • corpus luteum - ovarian endocrine organ from ovulating follicle, stimulated by hCG and supports early pregnancy by secreting progesterone, 17β-progesterone, estradiol and androstenedione.
  • corticosteroid binding globulin - (CBG) binds and transports glucocorticoids in the plasma. Globin is synthesised in the liver. adrenal
  • dihydrotestosterone - (DHT) steroidal hormone made locally by 5-alpha reductase conversion of testosterone into a more active form in genital effects.
  • dehydroepiandrosterone - (DHEA, androstenolone) adrenal cortex, gonads and brain make this steroid intermediate that may also have adult hormonal functions.
  • dehydroepiandrosterone sulphate - (DHEAS, DHEA-S) fetal adrenal cortex makes this inactive precursor of a steroid hormone.
  • dydrogesterone - clinical oral retrosteroid structurally related to progesterone, with a greater bioavailability and selectivity for the progesterone receptor.
  • estrogen (oestrogen) family of female steroidal hormones - estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4) synthesised from testosterone and androstenedione, by aromatase. Also produced in male testis, and required for genital development (PMID 29438493)
  • estrone (E1) - steroid hormone with weak estrogenic activity.
  • estradiol (E2) - (oestradiol) estrogen steroid hormone with main estrogenic female activity.
  • estriol (E3) - (oestriol) steroid hormone with weak estrogenic activity.
  • estetrol (E4) (oestetrol) steroid hormone with weak estrogenic activity produced only during pregnancy.
  • follicle stimulating hormone - (FSH) pituitary glycoprotein hormone secreted by gonadotrophs (basophilic cell subgroup) acts on gametogenesis and other systems in both males and females. Females, acts on the ovary to stimulate follicle development. Negative feedback by inhibin from the developing follicle decreases FSH secretion. Males, acts on the testis Sertoli cells to increase androgen-binding protein (ABP) that binds androgens and has a role in spermatogenesis.
  • growth hormone - (GH) pituitary, peptide hormone that stimulates tissue and skeletal growth. In the ovary, growth hormone also increases granulosa cell FSH-dependent E2 production.
  • growth hormone releasing hormone - (GHRH) hypothalamus‎, protein that activates growth hormone synthesis and release from the anterior pituitary.
  • human chorionic gonadotropin - (hCG) glycoprotein hormone with 2 subunits (alpha and beta joined non covalently). Similar in structure to luteinizing hormone (LH), hCG exists in multiple hormonal and non-endocrine agents (regular hCG, hyperglycosylated hCG and the free beta-subunit of hyperglycosylated hCG). PMID 19171054
  • human chorionic somatommotropin - (hCS, CSH, placental lactogen) Placental hormone is structurally similar to both growth hormone (GH) and prolactin (PRL} and binds strongly to PRL receptors but weakly to GH receptors. Role in stimulating maternal mammary gland development. endocrine placenta
  • interstitial cell - (Leydig cell) Male testis cell secrete the androgen testosterone, required for fetal male genital tract differentiation and masculinisation after puberty.
  • Leydig cell - (interstitial cell) Male testis cell secrete the androgen testosterone, beginning in the fetus. These cells are named after Franz von Leydig (1821 - 1908) a German scientist who histologically described these cells.
  • lutenizing hormone - (LH, gonadotropin, lutropin, Interstitial Cell Stimulating Hormone, ICSH) pituitary, glycoprotein hormone acts on the gonad and has a role in male and female reproduction. Female, increase in concentration during the menstrual cycle triggers ovulation. Male, stimulates testis interstital cell production of testosterone. Gonadotrophins have been used clinically in humans for the treatment of female infertility.
  • melaocyte stimulating hormone - (MSH) pituitary, peptide hormone pituitary
  • melatonin - (N-acetyl-5-methoxytryptamine) pineal amino acid amino (precursor tryptophan) hormone involved with the diurnal cycle, melatoinin levels are high in dark, low in daylight. Also acts as an antioxidant, free radical scavenger, and anti-inflammatory molecule.
  • prolactin - (PRL) pituitary, peptide hormone pituitary
  • parathyroid - endocrine gland through parathyroid hormone (PTH) regulates calcium and phosphate levels in conjunction with parafollicular cells of the thyroid gland (calcitonin) and Vitamin D, dietary or synthesized in the skin. Develops from pharyngeal endoderm, in this case the 3rd and 4th pharyngeal pouches.
  • parathyroid hormone - (PTH) parathyroid, peptide hormone parathyroid
  • synthetic ACTH test = (synacthen test) A diagnostic test to both measure the amount of cortisol in the body and to determine the ability to produce cortisol.
  • testosterone - testis ovary steroidal hormone. In males is the androgen which regulates genital (gonadal and tract), secondary sex characteristics and neural development. The steroid is converted to the active metabolite dihydrotestosterone (DHT) by the enzyme 5-alpha reductase for the genital effects and estradiol by the enzyme aromatase for the neural effects.
  • thyroid - endocrine gland located in the neck with a developmental role in neurological development and metabolism.
  • thyroid diverticulum - the primordium of the thyroid gland, beginning as an median endodermal thickening in the floor of pharynx between the pharyngeal pouch 1 and 2.
  • thyroid hormone - (TH) thyroid amino acid derivative with two main forms (T3, T4) regulates tissue metabolic activity.
  • thyroid stimulating hormone - (TSH) pituitary protein hormone
  • ultimobranchial body - historic term for the embryonic structure that forms the parafollicular cells (C cells) of the thyroid.
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Cite this page: Hill, M.A. (2018, June 21) Embryology Endocrine - Parathyroid Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Endocrine_-_Parathyroid_Development

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© Dr Mark Hill 2018, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G