Talk:Thymus Development: Difference between revisions

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http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0026795
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0026795
===Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sub lineage divergence===
PLoS Genet. 2011 Nov;7(11):e1002348. Epub 2011 Nov 3.
Nowell CS, Bredenkamp N, Tetélin S, Jin X, Tischner C, Vaidya H, Sheridan JM, Stenhouse FH, Heussen R, Smith AJ, Blackburn CC.
Source
MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
Abstract
The forkhead transcription factor Foxn1 is indispensable for thymus development, but the mechanisms by which it mediates thymic epithelial cell (TEC) development are poorly understood. To examine the cellular and molecular basis of Foxn1 function, we generated a novel and revertible hypomorphic allele of Foxn1. By varying levels of its expression, we identified a number of features of the Foxn1 system. Here we show that Foxn1 is a powerful regulator of TEC differentiation that is required at multiple intermediate stages of TE lineage development in the fetal and adult thymus. We find no evidence for a role for Foxn1 in TEC fate-choice. Rather, we show it is required for stable entry into both the cortical and medullary TEC differentiation programmes and subsequently is needed at increasing dosage for progression through successive differentiation states in both cortical and medullary TEC. We further demonstrate regulation by Foxn1 of a suite of genes with diverse roles in thymus development and/or function, suggesting it acts as a master regulator of the core thymic epithelial programme rather than regulating a particular aspect of TEC biology. Overall, our data establish a genetics-based model of cellular hierarchies in the TE lineage and provide mechanistic insight relating titration of a single transcription factor to control of lineage progression. Our novel revertible hypomorph system may be similarly applied to analyzing other regulators of development.
PMID 22072979


==2010==
==2010==

Revision as of 14:34, 20 February 2012

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Cite this page: Hill, M.A. (2024, March 28) Embryology Thymus Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Thymus_Development

2012

2011

A focused in situ hybridization screen identifies candidate transcriptional regulators of thymic epithelial cell development and function

PLoS One. 2011;6(11):e26795. Epub 2011 Nov 7.

Wei Q, Condie BG. Source Department of Genetics, University of Georgia, Athens, Georgia, United States of America.

Abstract

BACKGROUND: Thymic epithelial cells (TECs) are necessary for normal T cell development. Currently, one transcription factor, Foxn1 is known to be necessary for the progression of fetal TEC differentiation. However, some aspects of fetal TEC differentiation occur in Foxn1 mutants, suggesting the existence of additional transcriptional regulators of TEC differentiation. The goal of this study was to identify some of the additional candidate transcription factors that may be involved in the specification and/or differentiation of TECs during fetal development. METHODOLOGY/PRINCIPAL FINDINGS: We identified candidate fetal TEC transcriptional regulators via data and text mining. From our data mining we selected the transcription factors Foxg1, Isl1, Gata3, Nkx2-5, Nkx2-6 and Sox2 for further studies. Whole mount in situ hybridizations confirmed the expression of these transcription factors within subdomains of the third pharyngeal pouch from E9.5-E10.5. By E11.5 days Foxg1 and Isl1 transcripts were the only mRNAs from this group of genes detected exclusively within the thymus domain of the third pouch. Based on this initial in situ hybridization analysis, we focused on defining the expression of Foxg1 and Isl1 during multiple stages of thymus development and TEC differentiation. We found that Foxg1 and Isl1 are specifically expressed in differentiating TECs during fetal and postnatal stages of thymus development. In addition, we found differential expression of Islet1 and Foxn1 within the fetal and postnatal TEC population. CONCLUSIONS/SIGNIFICANCE: Our studies have identified two developmental transcription factors that are excellent candidate regulators of thymic epithelial cell specification and differentiation during fetal development. Our results suggest that Foxg1 and Isl1 may play a role in the regulation of TEC differentiation during fetal and postnatal stages. Our results also demonstrate heterogeneity of TECs marked by the differential expression of transcription factors, potentially providing new insights into the regulation of TEC differentiation.

PMID 22087235

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0026795

Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sub lineage divergence

PLoS Genet. 2011 Nov;7(11):e1002348. Epub 2011 Nov 3.

Nowell CS, Bredenkamp N, Tetélin S, Jin X, Tischner C, Vaidya H, Sheridan JM, Stenhouse FH, Heussen R, Smith AJ, Blackburn CC. Source MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

Abstract

The forkhead transcription factor Foxn1 is indispensable for thymus development, but the mechanisms by which it mediates thymic epithelial cell (TEC) development are poorly understood. To examine the cellular and molecular basis of Foxn1 function, we generated a novel and revertible hypomorphic allele of Foxn1. By varying levels of its expression, we identified a number of features of the Foxn1 system. Here we show that Foxn1 is a powerful regulator of TEC differentiation that is required at multiple intermediate stages of TE lineage development in the fetal and adult thymus. We find no evidence for a role for Foxn1 in TEC fate-choice. Rather, we show it is required for stable entry into both the cortical and medullary TEC differentiation programmes and subsequently is needed at increasing dosage for progression through successive differentiation states in both cortical and medullary TEC. We further demonstrate regulation by Foxn1 of a suite of genes with diverse roles in thymus development and/or function, suggesting it acts as a master regulator of the core thymic epithelial programme rather than regulating a particular aspect of TEC biology. Overall, our data establish a genetics-based model of cellular hierarchies in the TE lineage and provide mechanistic insight relating titration of a single transcription factor to control of lineage progression. Our novel revertible hypomorph system may be similarly applied to analyzing other regulators of development.

PMID 22072979

2010

A novel role for transcription factor Lmo4 in thymus development through genetic interaction with Cited2

Dev Dyn. 2010 Jul;239(7):1988-94.

Michell AC, Bragança J, Broadbent C, Joyce B, Franklyn A, Schneider JE, Bhattacharya S, Bamforth SD.

Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, United Kingdom. Abstract Deletion of the transcriptional modulator Cited2 in the mouse results in embryonic lethality, cardiovascular malformations, adrenal agenesis, cranial ganglia fusion, exencephaly, and left-right patterning defects, all seen with a varying degree of penetrance. The phenotypic heterogeneity, observed on different genetic backgrounds, indicates the existence of both genetic and environmental modifiers. Mice lacking the LIM domain-containing protein Lmo4 share specific phenotypes with Cited2 null embryos, such as embryonic lethality, cranial ganglia fusion, and exencephaly. These shared phenotypes suggested that Lmo4 may be a potential genetic modifier of the Cited2 phenotype. Examination of Lmo4-deficient embryos revealed partially penetrant cardiovascular malformations and hypoplastic thymus. Examination of Lmo4;Cited2 compound mutants indicated that there is a genetic interaction between Cited2 and Lmo4 in control of thymus development. Our data suggest that this may occur, in part, through control of expression of a common target gene, Tbx1, which is necessary for normal thymus development.

(c) 2010 Wiley-Liss, Inc. PMID: 20549734

Thymic stromal lymphopoietin

Ann N Y Acad Sci. 2010 Jan;1183:13-24.

He R, Geha RS.

Division of Immunology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine expressed in skin, gut, lungs, and thymus. TSLP signals via a TSLP receptor (TSLPR), a heterodimer of the IL-7 receptor alpha chain and the TSLPR chain. The TSLPR chain is closely related to the common receptor gamma chain that is expressed on a wide range of cell types in the adaptive and innate immune system. TSLP exerts a profound influence on the polarization of dendritic cells to drive T helper (Th) 2 cytokine production. TSLP also directly promotes T-cell proliferation in response to T-cell receptor activation and Th2 cytokine production and supports B-cell expansion and differentiation. TSLP further amplifies Th2 cytokine production by mast cells and natural killer T cells. These properties confer on TSLP a critical role in driving Th2-mediated inflammation. This role is supported by the finding that TSLP expression is upregulated in keratinocytes of atopic dermatitis skin lesions and in bronchial epithelial cells in asthma.

PMID: 20146705

http://www.ncbi.nlm.nih.gov/pubmed/20146705

2009

Gene expression profile of the third pharyngeal pouch reveals role of mesenchymal MafB in embryonic thymus development

Blood. 2009 Mar 26;113(13):2976-87. Epub 2009 Jan 22.

Sultana DA, Tomita S, Hamada M, Iwanaga Y, Kitahama Y, Khang NV, Hirai S, Ohigashi I, Nitta S, Amagai T, Takahashi S, Takahama Y.

Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima, Japan.

Abstract

The thymus provides a microenvironment that induces the differentiation of T-progenitor cells into functional T cells and that establishes a diverse yet self-tolerant T-cell repertoire. However, the mechanisms that lead to the development of the thymus are incompletely understood. We report herein the results of screening for genes that are expressed in the third pharyngeal pouch, which contains thymic primordium. Polymerase chain reaction (PCR)-based cDNA subtraction screening for genes expressed in microdissected tissues of the third pharyngeal pouch rather than the second pharyngeal arch yielded one transcription factor, MafB, which was predominantly expressed in CD45(-)IA(-)PDGFRalpha(+) mesenchymal cells and was detectable even in the third pharyngeal pouch of FoxN1-deficient nude mice. Interestingly, the number of CD45(+) cells that initially accumulated in the embryonic thymus was significantly decreased in MafB-deficient mice. Alterations of gene expression in the embryonic thymi of MafB-deficient mice included the reduced expression of Wnt3 and BMP4 in mesenchymal cells and of CCL21 and CCL25 in epithelial cells. These results suggest that MafB expressed in third pharyngeal pouch mesenchymal cells critically regulates lymphocyte accumulation in the embryonic thymus.

PMID: 19164599

2008

Neural crest origin of perivascular mesenchyme in the adult thymus

J Immunol. 2008 Apr 15;180(8):5344-51.

Müller SM, Stolt CC, Terszowski G, Blum C, Amagai T, Kessaris N, Iannarelli P, Richardson WD, Wegner M, Rodewald HR.

Institute for Immunology, University of Ulm, Ulm, Germany.

Abstract

The endodermal epithelial thymus anlage develops in tight association with neural crest (NC)-derived mesenchyme. This epithelial-NC interaction is crucial for thymus development, but it is not known how NC supports thymus development or whether NC cells or their progeny make any significant contribution to the adult thymus. By nude mouse blastocyst complementation and by cell surface phenotype, we could previously separate thymus stroma into Foxn1-dependent epithelial cells and a Foxn1-independent mesenchymal cell population. These mesenchymal cells expressed vascular endothelial growth factor-A, and contributed to thymus vascularization. These data suggested a physical or functional association with thymic blood vessels, but the origin, location in the thymus, and function of these stromal cells remained unknown. Using a transgenic mouse expressing Cre recombinase in premigratory NC (Sox10-Cre), we have now fate-mapped the majority of these adult mesenchymal cells to a NC origin. NC-derived cells represent tightly vessel-associated pericytes that are sandwiched between endothelium and epithelium along the entire thymus vasculature. The ontogenetic, phenotypic, and positional definition of this distinct perivascular mesenchymal compartment provides a cellular basis for the role of NC in thymus development and possibly maintenance, and might be useful to address properties of the endothelial-epithelial barrier in the adult thymus.

PMID: 18390716

http://www.jimmunol.org/content/180/8/5344.long

2007

Ontogeny of intrinsic innervation in the human thymus and spleen

J Histochem Cytochem. 2007 Aug;55(8):813-20. Epub 2007 Apr 16.

Anagnostou VK, Doussis-Anagnostopoulou I, Tiniakos DG, Karandrea D, Agapitos E, Karakitsos P, Kittas C.

Laboratory of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Str, 11527 Athens, Greece. aisantha@hotmail.com Abstract The ontogeny of the innervation of human lymphoid organs has not been studied in detail. Our aim was to assess the nature and distribution of parenchymal nerves in human fetal thymus and spleen. We used the peroxidase immunohistochemical technique with antibodies specific to neuron-specific enolase (NSE), neurofilaments (NF), PGP9.5, S100 protein, and tyrosine hydroxylase (TH) and evaluated our results with image analysis. In human fetal thymus, NSE-, NF-, S100-, PGP9.5-, and TH-positive nerves were identified associated with large blood vessels from 18 gestational weeks (gw) onwards, increasing in density during development. Their branches penetrated the septal areas at 20 gw, reaching the cortex and the corticomedullary junction between 20 and 23 gw. Few nerve fibers were seen in the medulla in close association with Hassall's corpuscles. In human fetal spleen, NSE-, NF-, S100-, PGP9.5-, and TH-positive nerve fibers were localized in the connective tissue surrounding the splenic artery at 18 gw. Perivascular NSE-, NF-, S100-, PGP9.5-, and TH-positive nerve fibers were seen extending into the white pulp, mainly in association with the central artery and its branches, increasing in density during gestation. Scattered NSE-, NF-, S100-, PGP9.5-, and TH-positive nerve fibers and endings were localized in the red pulp from 18 gw onward. The predominant perivascular distribution of most parenchymal nerves implies that thymic and splenic innervation may play an important functional role during intrauterine life.

PMID: 17438351

2006

Cellular and molecular events during early thymus development

Holländer G, Gill J, Zuklys S, Iwanami N, Liu C, Takahama Y. Immunol Rev. 2006 Feb;209:28-46. Review.

The thymic stromal compartment consists of several cell types that collectively enable the attraction, survival, expansion, migration, and differentiation of T-cell precursors. The thymic epithelial cells constitute the most abundant cell type of the thymic microenvironment and can be differentiated into morphologically, phenotypically, and functionally separate subpopulations of the postnatal thymus. All thymic epithelial cells are derived from the endodermal lining of the third pharyngeal pouch. Very soon after the formation of a thymus primordium and prior to its vascularization, thymic epithelial cells orchestrate the first steps of intrathymic T-cell development, including the attraction of lymphoid precursor cells to the thymic microenvironment. The correct segmentation of pharyngeal epithelial cells and their subsequent crosstalk with cells in the pharyngeal arches are critical prerequisites for the formation of a thymus anlage. Mutations in several transcription factors and their target genes have been informative to detail some of the complex mechanisms that control the development of the thymus anlage.

PMID: 16448532


The thymus is a common target organ in infectious diseases

PLoS Pathog. 2006 Jun;2(6):e62.

Savino W. Source Laboratory on Thymus Research, Department of Immunology, Oswaldo Cruz Institute, Inserm-Fiocruz Associated Laboratory of Immunology, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil. savino@fiocruz.br

Abstract

Infectious disease immunology has largely focused on the effector immune response, changes in the blood and peripheral lymphoid organs of infected individuals, and vaccine development. Studies of the thymus in infected individuals have been neglected, although this is progressively changing. The thymus is a primary lymphoid organ, able to generate mature T cells that eventually colonize secondary lymphoid organs, and is therefore essential for peripheral T cell renewal. Recent data show that normal thymocyte development and export can be altered as a result of an infectious disease. One common feature is the severe atrophy of the infected organ, mainly due to the apoptosis-related depletion of immature CD4+CD8+ thymocytes. Additionally, thymocyte proliferation is frequently diminished. The microenvironmental compartment of the thymus is also affected, particularly in acute infectious diseases, with a densification of the epithelial network and an increase in the deposition of extracellular matrix. In the murine model of Chagas disease, intrathymic chemokine production is also enhanced, and thymocytes from Trypanosoma cruzi-infected mice exhibit greater numbers of cell migration-related receptors for chemokines and extracellular matrix, as well as increased migratory responses to the corresponding ligands. This profile is correlated with the appearance of potentially autoreactive thymus-derived immature CD4+CD8+ T cells in peripheral organs of infected animals. A variety of infectious agents--including viruses, protozoa, and fungi--invade the thymus, raising the hypothesis of the generation of central immunological tolerance for at least some of the infectious agent-derived antigens. It seems clear that the thymus is targeted in a variety of infections, and that such targeting may have consequences on the behavior of peripheral T lymphocytes. In this context, thymus-centered immunotherapeutic approaches potentially represent a new tool for the treatment of severe infectious diseases.

PMID 16846255 PMC1483230


Introduction

Embryonic origins of the endocrine organs of the neck

The thymus has two origins for the lymphoid thymocytes and the thymic epithelial cells. The thymic epithelium begins as two flask-shape endodermal diverticula that form from the third pharyngeal pouch and extend lateralward and backward into the surrounding mesoderm and neural crest-derived mesenchyme in front of the ventral aorta. The immune system T cells are essential for responses against infections and much research concerns the postnatal development of T cells within the thymus.

Endocrine Links: Introduction | BGD Lecture | Science Lecture | Lecture Movie | pineal | hypothalamus‎ | pituitary | thyroid | parathyroid | thymus | pancreas | adrenal | endocrine gonad‎ | endocrine placenta | other tissues | Stage 22 | endocrine abnormalities | Hormones | Category:Endocrine
Historic Embryology - Endocrine  
1903 Islets of Langerhans | 1903 Pig Adrenal | 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 Adrenal | 1927 Hypophyseal fossa | 1930 Adrenal | 1932 Pineal Gland and Cysts | 1935 Hypophysis | 1935 Pineal | 1937 Pineal | 1935 Parathyroid | 1940 Adrenal | 1941 Thyroid | 1950 Thyroid Parathyroid Thymus | 1957 Adrenal

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1909 Lymph glands | 1912 Development of the Lymphatic System | 1918 Gray's Lymphatic Images | 1916 Pig Lymphatics | 1919 Chicken Lymphatic | 1921 Spleen | 1922 Pig Stomach Lymphatics | 1932 Cat Pharyngeal Tonsil | Historic Disclaimer

Some Recent Findings

  • Decision checkpoints in the thymus[1]"The development of T cells in the thymus involves several differentiation and proliferation events, during which hematopoietic precursors give rise to T cells ready to respond to antigen stimulation and undergo effector differentiation."

Thymus Development

Developing Human (stage 22)
Developing Human Thymus (stage 22)
  • Endoderm - third pharyngeal pouch
  • Week 6 - diverticulum elongates, hollow then solid, ventral cell proliferation
  • Thymic primordia - surrounded by neural crest mesenchyme, epithelia/mesenchyme interaction
  • Thymus - bone-marrow lymphocyte precursors become thymocytes, and subsequently mature into T lymphocytes (T cells)
  • Thymus hormones - thymosins stimulate the development and differentiation of T lymphocytes
Stage 13 image 058.jpg Stage 22 image 071.jpg
B2 Pharyngeal Arch Pouches 3 and 4 (stage 13) D1 Developing Human Thymus (stage 22)

Thymus Involution

A postnatal process defined as a decrease in the size, weight and activity of the gland with advancing age. In a recent review[2], thymic involution was described as a result of high levels of circulating sex hormones, in particular during puberty, and a lower population of precursor cells from the bone marrow and finally changes in the thymic microenvironment.

References

  1. <pubmed>20644572</pubmed>
  2. <pubmed>20354268 </pubmed>


Reviews

<pubmed>19582736</pubmed> <pubmed>18304000</pubmed> <pubmed>17876091</pubmed> <pubmed>16448532</pubmed>

Articles

<pubmed>17625108</pubmed>


Adult Histology

Terms

  • Hassall's corpuscle - thymic corpuscle.
  • Thymic corpuscle (=Hassall's corpuscle) a mass of concentric epithelioreticular cells found in the thymus. The number present and size tend to increase with thymus age. (see classical description of Hammar, J. A. 1903 Zur Histogenese und Involution der Thymusdriise. Anat. Anz., 27: 1909 Fiinfzig Jahre Thymusforschung. Ergebn. Anat. Entwickl-gesch. 19: 1-274.)
  • thymic epitheliocytes - reticular cells located in the thymus cortex that ensheathe the cortical capillaries, creating and maintain the microenvironment necessary for the development of T-lymphocytes in the cortex.
  • T lymphocyte (cell) - named after thymus, where they develop, the active cell is responsible for cell-mediated immunity. (More? Electron micrographs of nonactivate and activated lymphocytes)