Talk:Endocrine - Parathyroid Development
- Parathyroid Hormone - Increase calcium ions [Ca2+], stimulates osteoclasts, increase Ca GIT absorption (opposite effect to calcitonin)
- Adult Calcium and Phosphate - Daily turnover in human with dietary intake of 1000 mg/day
- secreted by chief cells
Principal cells cords of cells
10 Most Recent Papers
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<pubmed limit=5>Parathyroid Embryology</pubmed>
<pubmed limit=5>Parathyroid Development</pubmed>
Tissue-specific roles for sonic hedgehog signaling in establishing thymus and parathyroid organ fate
Bain VE, Gordon J, O'Neil JD, Ramos I, Richie ER & Manley NR. (2016). Tissue-specific roles for sonic hedgehog signaling in establishing thymus and parathyroid organ fate. Development , 143, 4027-4037. PMID: 27633995 DOI.
Bain VE1, Gordon J1, O'Neil JD1, Ramos I1, Richie ER2, Manley NR3. Author information Abstract The thymus and parathyroids develop from third pharyngeal pouch (3rd pp) endoderm. Our previous studies show that Shh null mice have smaller, aparathyroid primordia in which thymus fate specification extends into the pharynx. SHH signaling is active in both dorsal pouch endoderm and neighboring neural crest (NC) mesenchyme. It is unclear which target tissue of SHH signaling is required for the patterning defects in Shh mutants. Here, we used a genetic approach to ectopically activate or delete the SHH signal transducer Smo in either pp endoderm or NC mesenchyme. Although no manipulation recapitulated the Shh null phenotype, manipulation of SHH signaling in either the endoderm or NC mesenchyme had direct and indirect effects on both cell types during fate specification and organogenesis. SHH pathway activation throughout pouch endoderm activated ectopic Tbx1 expression and partially suppressed the thymus-specific transcription factor Foxn1, identifying Tbx1 as a key target of SHH signaling in the 3rd pp. However, ectopic SHH signaling was insufficient to expand the GCM2-positive parathyroid domain, indicating that multiple inputs, some of which might be independent of SHH signaling, are required for parathyroid fate specification. These data support a model in which SHH signaling plays both positive and negative roles in patterning and organogenesis of the thymus and parathyroids. KEYWORDS: Endoderm; Morphogenesis; Mouse; Neural crest; Parathyroid; Smoothened; Sonic hedgehog; Thymus
Notch and Hedgehog in the thymus/parathyroid common primordium: Crosstalk in organ formation
Figueiredo M, Silva JC, Santos AS, Proa V, Alcobia I, Zilhão R, Cidadão A & Neves H. (2016). Notch and Hedgehog in the thymus/parathyroid common primordium: Crosstalk in organ formation. Dev. Biol. , 418, 268-82. PMID: 27544844 DOI.
Figueiredo M1, Silva JC2, Santos AS3, Proa V4, Alcobia I5, Zilhão R6, Cidadão A7, Neves H8. Author information Abstract The avian thymus and parathyroids (T/PT) common primordium derives from the endoderm of the third and fourth pharyngeal pouches (3/4PP). The molecular mechanisms that govern T/PT development are not fully understood. Here we study the effects of Notch and Hedgehog (Hh) signalling modulation during common primordium development using in vitro, in vivo and in ovo approaches. The impairment of Notch activity reduced Foxn1/thymus-fated and Gcm2/Pth/parathyroid-fated domains in the 3/4PP and further compromised the development of the parathyroid glands. When Hh signalling was abolished, we observed a reduction in the Gata3/Gcm2- and Lfng-expression domains at the median/anterior and median/posterior territories of the pouches, respectively. In contrast, the Foxn1 expression-domain at the dorsal tip of the pouches expanded ventrally into the Lfng-expression domain. This study offers novel evidence on the role of Notch signalling in T/PT common primordium development, in an Hh-dependent manner. KEYWORDS: Avian; Hedgehog; Notch; Pharyngeal pouches; Thymus/parathyroids common primordium PMID: 27544844 DOI: 10.1016/j.ydbio.2016.08.012
Multiple roles for HOXA3 in regulating thymus and parathyroid differentiation and morphogenesis in mouse
Development. 2014 Oct;141(19):3697-708. doi: 10.1242/dev.110833. Epub 2014 Sep 5.
Chojnowski JL1, Masuda K1, Trau HA1, Thomas K2, Capecchi M3, Manley NR4.
Hoxa3 was the first Hox gene to be mutated by gene targeting in mice and is required for the development of multiple endoderm and neural crest cell (NCC)-derived structures in the pharyngeal region. 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 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. These data show that Hoxa3 has multiple complex and tissue-specific functions during patterning, differentiation and morphogenesis of the thymus and parathyroids. © 2014. Published by The Company of Biologists Ltd. KEYWORDS: Hoxa3; Mouse; Parathyroid; Thymus
Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions
PLoS Genet. 2010 Dec 23;6(12):e1001251.
Liu Z, Farley A, Chen L, Kirby BJ, Kovacs CS, Blackburn CC, Manley NR. Source Department of Genetics, University of Georgia, Athens, Georgia, United States of America.
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. We found that the lethality of aparathyroid Gcm2⁻/⁻ mutants was affected by genetic background without relation to serum PTH levels, suggesting a need to reconsider the physiological function of thymic PTH. We identified two sources of extra-parathyroid PTH in wild-type mice. Incomplete separation of the parathyroid and thymus organs during organogenesis resulted in misplaced, isolated parathyroid cells that were often attached to the thymus; this was the major source of thymic PTH in normal mice. Analysis of thymus and parathyroid organogenesis in human embryos showed a broadly similar result, indicating that these results may provide insight into human parathyroid development. In addition, medullary thymic epithelial cells (mTECs) express PTH in a Gcm2-independent manner that requires TEC differentiation and is consistent with expression as a self-antigen for negative selection. Genetic or surgical removal of the thymus indicated that thymus-derived PTH in Gcm2⁻/⁻ mutants did not provide auxiliary endocrine function. 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."
Parathyroid Hormone Stimulates Circulating Osteogenic Cells in Hypoparathyroidism
J Clin Endocrinol Metab. 2010 Sep 29. [Epub ahead of print]
Rubin MR, Manavalan JS, Dempster DW, Shah J, Cremers S, Kousteni S, Zhou H, McMahon DJ, Kode A, Sliney J, Shane E, Silverberg SJ, Bilezikian JP.
Department of Medicine, Division of Endocrinology, Metabolic Bone Diseases Unit, College of Physicians and Surgeons, Columbia University, New York, New York 10032. Abstract Context: The osteoanabolic properties of PTH may be due to increases in the number and maturity of circulating osteogenic cells. Hypoparathyroidism is a useful clinical model because this hypothesis can be tested by administering PTH. Objective: The objective of the study was to characterize circulating osteogenic cells in hypoparathyroid subjects during 12 months of PTH (1-84) administration. Design: Osteogenic cells were characterized using flow cytometry and antibodies against osteocalcin, an osteoblast-specific protein product, and stem cell markers CD34 and CD146. Changes in bone formation from biochemical markers and quadruple-labeled transiliac crest bone biopsies (0 and 3 month time points) were correlated with measurements of circulating osteogenic cells. Setting: The study was conducted at a clinical research center. Patients: Nineteen control and 19 hypoparathyroid patients were included in the study. Intervention: Intervention included the administration of PTH (1-84). Results: Osteocalcin-positive cells were lower in hypoparathyroid subjects than controls (0.7 ± 0.1 vs. 2.0 ± 0.1%; P < 0.0001), with greater coexpression of the early cell markers CD34 and CD146 among the osteocalcin-positive cells in the hypoparathyroid subjects (11.0 ± 1.0 vs. 5.6 ± 0.7%; P < 0.001). With PTH (1-84) administration, the number of osteogenic cells increased 3-fold (P < 0.0001), whereas the coexpression of the early cell markers CD34 and CD146 decreased. Increases in osteogenic cells correlated with circulating and histomorphometric indices of osteoblast function: N-terminal propeptide of type I procollagen (R(2) = 0.4, P ≤ 0.001), bone-specific alkaline phosphatase (R(2) = 0.3, P < 0.001), osteocalcin (R(2) = 0.4, P < 0.001), mineralized perimeter (R(2) = 0.5, P < 0.001), mineral apposition rate (R(2) = 0.4, P = 0.003), and bone formation rate (R(2) = 0.5, P < 0.001). Conclusions: It is likely that PTH stimulates bone formation by stimulating osteoblast development and maturation. Correlations between circulating osteogenic cells and histomorphometric indices of bone formation establish that osteoblast activity is being identified by this methodology.
PMID: 20881259 http://www.ncbi.nlm.nih.gov/pubmed/20881259
The Wnt/beta-catenin pathway interacts differentially with PTHrP signaling to control chondrocyte hypertrophy and final maturation.
Guo X, Mak KK, Taketo MM, Yang Y. PLoS One. 2009 Jun 26;4(6):e6067.
--Mark Hill 00:02, 3 October 2010 (UTC) - Good images of mouse bone development and model figure.
Sequential proliferation, hypertrophy and maturation of chondrocytes are required for proper endochondral bone development and tightly regulated by cell signaling. The canonical Wnt signaling pathway acts through beta-catenin to promote chondrocyte hypertrophy whereas PTHrP signaling inhibits it by holding chondrocytes in proliferating states. Here we show by genetic approaches that chondrocyte hypertrophy and final maturation are two distinct developmental processes that are differentially regulated by Wnt/beta-catenin and PTHrP signaling. Wnt/beta-catenin signaling regulates initiation of chondrocyte hypertrophy by inhibiting PTHrP signaling activity, but it does not regulate PTHrP expression. In addition, Wnt/beta-catenin signaling regulates chondrocyte hypertrophy in a non-cell autonomous manner and Gdf5/Bmp signaling may be one of the downstream pathways. Furthermore, Wnt/beta-catenin signaling also controls final maturation of hypertrophic chondrocytes, but such regulation is PTHrP signaling-independent.
Mol Biol Cell. 2009 Nov;20(21):4541-51. Epub 2009 Sep 16.
Amano K, Hata K, Sugita A, Takigawa Y, Ono K, Wakabayashi M, Kogo M, Nishimura R, Yoneda T.
Department of Molecular and Cellular Biology, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan. Abstract Sox9 is a transcription factor that plays an essential role in chondrogenesis and has been proposed to inhibit the late stages of endochondral ossification. However, the molecular mechanisms underlying the regulation of chondrocyte maturation and calcification by Sox9 remain unknown. In this study, we attempted to clarify roles of Sox9 in the late stages of chondrocyte differentiation. We found that overexpression of Sox9 alone or Sox9 together with Sox5 and Sox6 (Sox5/6/9) inhibited the maturation and calcification of murine primary chondrocytes and up-regulated parathyroid hormone-related protein (PTHrP) expression in primary chondrocytes and the mesenchymal cell line C3H10T1/2. Sox5/6/9 stimulated the early stages of chondrocyte proliferation and development. In contrast, Sox5/6/9 inhibited maturation and calcification of chondrocytes in organ culture. The inhibitory effects of Sox5/6/9 were rescued by treating with anti-PTHrP antibody. Moreover, Sox5/6/9 bound to the promoter region of the PTHrP gene and up-regulated PTHrP gene promoter activity. Interestingly, we also found that the Sox9 family members functionally collaborated with Ihh/Gli2 signaling to regulate PTHrP expression and chondrocyte differentiation. Our results provide novel evidence that Sox9 family members mediate endochondral ossification by up-regulating PTHrP expression in association with Ihh/Gli2 signaling.
Alman BA, Wunder JS. Ann N Y Acad Sci. 2008 Nov;1144:36-41. Review. PMID: 19076361
Massfelder T, Helwig JJ. Endocrinology. 1999 Apr;140(4):1507-10. Review. No abstract available. PMID: 10098481
Karaplis AC, Vautour L. Curr Opin Nephrol Hypertens. 1997 Jul;6(4):308-13. Review. PMID: 9263678
Parathyroid hormone-related protein and its role in pregnancy, lactation, and neonatal growth and development. Cooper CW. Eur J Endocrinol. 1997 May;136(5):465-6. Review. No abstract available. PMID: 9186263
Parathyroid hormone-related protein. An analog of parathyroid hormone involved in regulation of growth, development, and gestation. Rizzoli R. Rev Rhum Engl Ed. 1996 Feb;63(2):79-82. Review. No abstract available. PMID: 8689291
Orphanet J Rare Dis. 2010 May 21;5:11.
Galanello R, Origa R.
Dipartimento di Scienze Biomediche e Biotecnologie- Università di Cagliari, Ospedale Regionale, Microcitemie ASL Cagliari, Cagliari, Italy. email@example.com Abstract Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with thalassemia major usually present within the first two years of life with severe anemia, requiring regular red blood cell (RBC) transfusions. Findings in untreated or poorly transfused individuals with thalassemia major, as seen in some developing countries, are growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. Regular transfusion therapy leads to iron overload-related complications including endocrine complication (growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands), dilated myocardiopathy, liver fibrosis and cirrhosis). Patients with thalassemia intermedia present later in life with moderate anemia and do not require regular transfusions. Main clinical features in these patients are hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis and its complications (osteoporosis, masses of erythropoietic tissue that primarily affect the spleen, liver, lymph nodes, chest and spine, and bone deformities and typical facial changes), gallstones, painful leg ulcers and increased predisposition to thrombosis. Thalassemia minor is clinically asymptomatic but some subjects may have moderate anemia. Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0) synthesis of the beta chains of hemoglobin (Hb). Transmission is autosomal recessive; however, dominant mutations have also been reported. Diagnosis of thalassemia is based on hematologic and molecular genetic testing. Differential diagnosis is usually straightforward but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as juvenile myelomonocytic leukemia and aplastic anemia). Genetic counseling is recommended and prenatal diagnosis may be offered. Treatment of thalassemia major includes regular RBC transfusions, iron chelation and management of secondary complications of iron overload. In some circumstances, spleen removal may be required. Bone marrow transplantation remains the only definitive cure currently available. Individuals with thalassemia intermedia may require splenectomy, folic acid supplementation, treatment of extramedullary erythropoietic masses and leg ulcers, prevention and therapy of thromboembolic events. Prognosis for individuals with beta-thalassemia has improved substantially in the last 20 years following recent medical advances in transfusion, iron chelation and bone marrow transplantation therapy. However, cardiac disease remains the main cause of death in patients with iron overload.