Talk:Endocrine - Thymus Development

Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells

Depreter MG, Blair NF, Gaskell TL, Nowell CS, Davern K, Pagliocca A, Stenhouse FH, Farley AM, Fraser A, Vrana J, Robertson K, Morahan G, Tomlinson SR, Blackburn CC. Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):961-6. Epub 2008 Jan 14.

The thymus is essential for a functional immune system, because the thymic stroma uniquely supports T lymphocyte development. We have previously identified the epithelial progenitor population from which the thymus arises and demonstrated its ability to generate an organized functional thymus upon transplantation. These thymic epithelial progenitor cells (TEPC) are defined by surface determinants recognized by the mAbs MTS20 and MTS24, which were also recently shown to identify keratinocyte progenitor cells in the skin. However, the biochemical nature of the MTS20 and MTS24 determinants has remained unknown. Here we show, via expression profiling of fetal mouse TEPC and their differentiated progeny and subsequent analyses, that both MTS20 and MTS24 specifically bind an orphan protein of unknown function, Placenta-expressed transcript (Plet)-1. In the postgastrulation embryo, Plet-1 expression is highly restricted to the developing pharyngeal endoderm and mesonephros until day 11.5 of embryogenesis, consistent with the MTS20 and MTS24 staining pattern; both MTS20 and MTS24 specifically bind cell lines transfected with Plet-1; and antibodies to Plet-1 recapitulate MTS20/24 staining. In adult tissues, we demonstrate expression in a number of sites, including mammary and prostate epithelia and in the pancreas, where Plet-1 is specifically expressed by the major duct epithelium, providing a specific cell surface marker for this putative reservoir of pancreatic progenitor/stem cells. Plet-1 will thus provide an invaluable tool for genetic analysis of the lineage relationships and molecular mechanisms operating in the development, homeostasis, and injury in several organ/tissue systems.

PMID: 18195351 http://www.ncbi.nlm.nih.gov/pubmed/18195351

Wnt4 and LAP2alpha as pacemakers of thymic epithelial senescence

Kvell K, Varecza Z, Bartis D, Hesse S, Parnell S, Anderson G, Jenkinson EJ, Pongracz JE. PLoS One. 2010 May 18;5(5):e10701. PMID: 20502698

Foxn1 is essential for vascularization of the murine thymus anlage

Mori K, Itoi M, Tsukamoto N, Amagai T. Cell Immunol. 2010;260(2):66-9. Epub . PMID: 19853842

Lessons from thymic epithelial heterogeneity: FoxN1 and tissue-restricted gene expression by extrathymic, endodermally derived epithelium

Dooley J, Erickson M, Farr AG. J Immunol. 2009 Oct 15;183(8):5042-9. Epub 2009 Sep 28. PMID: 19786540

A roadmap for thymic epithelial cell development

Anderson G, Jenkinson EJ, Rodewald HR. Eur J Immunol. 2009 Jul;39(7):1694-9. Review. PMID: 19582736

Foxa2 regulates polarity and epithelialization in the endoderm germ layer of the mouse embryo

Burtscher I, Lickert H. Development. 2009 Mar;136(6):1029-38. PMID: 19234065

Characterization of the thymic IL-7 niche in vivo

Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1512-7. Epub 2009 Jan 21.

Alves NL, Richard-Le Goff O, Huntington ND, Sousa AP, Ribeiro VS, Bordack A, Vives FL, Peduto L, Chidgey A, Cumano A, Boyd R, Eberl G, Di Santo JP.

Cytokines and Lymphoid Development Unit, Lymphocyte Development Unit, Plate-Forme Technologique Centre d'Ingénierie Génétique Murine, and Laboratory of Lymphoid Tissue Development, Institut Pasteur, Paris, France. Abstract The thymus represents the "cradle" for T cell development, with thymic stroma providing multiple soluble and membrane cues to developing thymocytes. Although IL-7 is recognized as an essential factor for thymopoiesis, the "environmental niche" of thymic IL-7 activity remains poorly characterized in vivo. Using bacterial artificial chromosome transgenic mice in which YFP is under control of IL-7 promoter, we identify a subset of thymic epithelial cells (TECs) that co-express YFP and high levels of Il7 transcripts (IL-7(hi) cells). IL-7(hi) TECs arise during early fetal development, persist throughout life, and co-express homeostatic chemokines (Ccl19, Ccl25, Cxcl12) and cytokines (Il15) that are critical for normal thymopoiesis. In the adult thymus, IL-7(hi) cells localize to the cortico-medullary junction and display traits of both cortical and medullary TECs. Interestingly, the frequency of IL-7(hi) cells decreases with age, suggesting a mechanism for the age-related thymic involution that is associated with declining IL-7 levels. Our temporal-spatial analysis of IL-7-producing cells in the thymus in vivo suggests that thymic IL-7 levels are dynamically regulated under distinct physiological conditions. This IL-7 reporter mouse provides a valuable tool to further dissect the mechanisms that govern thymic IL-7 expression in vivo.

PMID: 19164539

On the role of Eph signalling in thymus histogenesis; EphB2/B3 and the organizing of the thymic epithelial network

García-Ceca J, Jiménez E, Alfaro D, Cejalvo T, Chumley MJ, Henkemeyer M, Muñoz JJ, Zapata AG. Int J Dev Biol. 2009;53(7):971-82.

PMID: 19598115 http://www.ncbi.nlm.nih.gov/pubmed/19598115

In the current study, we extend our own previous results on the thymocyte phenotype of EphB2 and/or EphB3 deficient mice by analyzing the phenotype and the histological organization of their thymic epithelial stroma. All studied adult EphB-deficient thymi showed profound alterations with respect to the wild-type (WT) ones. Each mutant exhibited a specific phenotype, but also showed common features including occurrence of K5+K8+MTS10+ immature medullary epithelial cells, numerous K5-K8-MTS20+ cells and K5+K8+ cells in the thymic cortex and cortical and medullary K5-K8- areas devoid of epithelial cell markers. In addition, comparative analysis of WT and EphB-deficient embryonic and newborn thymi demonstrated that the observed adult phenotype was a consequence of the gradual accumulation of early phenotypic and morphological defects, becoming more severe at the end of embryonic life and in newborn animals. Together, these results confirm a role for EphB2 and EphB3 in thymus morphogenesis. The obtained data are discussed from the point of view of the recognized role played by these two Ephs in the homeostasis of other epithelia and their possible relationships with molecules known to be involved in thymic epithelial cell development.

Wiki text

The two main components of the thymus, the lymphoid thymocytes and the thymic epithelial cells, have distinct developmental origins. The thymic epithelium is the first to develop, and appears in the form of two flask-shape endodermal diverticula, which arise, one on either side, from the third branchial pouch (pharyngeal pouch), and extend lateralward and backward into the surrounding mesoderm and neural crest-derived mesenchyme in front of the ventral aorta.

Here they meet and become joined to one another by connective tissue, but there is never any fusion of the thymus tissue proper. The pharyngeal opening of each diverticulum is soon obliterated, but the neck of the flask persists for some time as a cellular cord. By further proliferation of the cells lining the flask, buds of cells are formed, which become surrounded and isolated by the invading mesoderm. Additional portions of thymus tissue are sometimes developed from the fourth branchial pouches.

During the late stages of the development of the thymic epithelium, hematopoietic bone-marrow precursors migrate into the thymus. Normal thymic development thereafter is dependant on the interaction between the thymic epithelium and the hematopoietic thymocytes.