Mechanisms of thymus organogenesis and morphogenesis

Jack, Gordon; Manley, Nancy R.

doi:10.1242/dev.059998

Cited by 248 publications

(239 citation statements)

References 120 publications

(146 reference statements)

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“…2A). At the right side of the pharyngeal region the number of EpCAM + EGFP + cells appeared to be higher, consistent with earlier observations that there is asymmetry in developmental timing between the two sides of the embryo [32]. Next, sections of whole E11.5 embryos were analyzed.…”

Section: Lgr5 Marks a Subset Of Fetal Tecs In Early Thymus Developmentsupporting

confidence: 85%

Characterization of Lgr5‐positive epithelial cells in the murine thymus

et al. 2013

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Leucine-rich repeat-containing G protein-coupled receptor (Lgr)5 is a marker for epithelial stem cells in the adult intestine of mice. Lgr5 transcripts have also been detected in the developing murine thymus, leading to speculation that Lgr5 is a marker for the longsought stem cell of the thymus. To address the nature of the Lgr5-expressing thymic epithelial cells (TECs), we used Lgr5-GFP reporter mice. We show that epithelial cells expressing Lgr5 protein are present in the fetal thymus during a specific developmental window yet are no longer detectable at birth. To analyze the function of the Lgr5 protein during thymus development, we generated Lgr5 −/− mice. These experiments unequivocally show that thymus development is not perturbed in the absence of Lgr5, that all TEC subsets develop in Lgr5 −/− mice and that T cells are produced in the expected ratios. Finally, by using an inducible lineage tracing system to track the progeny of Lgr5 + fetal TECs in vivo, we demonstrated that Lgr5 + fetal TECs have no detectable progeny in the later fetal thymus. In sum, we show that presence of the Lgr5 protein is not a prerequisite for proper thymus organogenesis. Keywords:Fetal thymus r Lgr5 r Lineage tracing r Thymic epithelial cells IntroductionThymic epithelial cells (TECs) form a 3D network that is essential for the proper proliferation, differentiation, and selection of developing thymocytes. Epithelial derived factors include growth factors, differentiation signals, and self-antigens expressed via MHC class I (MHCI) and MHC class II (MHCII) (reviewed in [1]). Presentation of self-antigens on TECs [2-5], the exact timing, affinity, and cofactors for the physiological contact between TECs and developing T cells (reviewed in [6]) is fundamental for proper T-cell development.The murine thymus originates from the third pharyngeal pouch at day E9.5 of embryonic development and is solely derived from the endoderm [7]. Specification of the thymus involves the sequential upregulation of important transcription factors (Hoxa3, Eya1, Rae2, chordin, and BMP; (reviewed in [8]) eventually leading to the expression of the thymic-specific transcription Correspondence: Prof. Jan J. Cornelissen e-mail: J.Cornelissen@erasmusmc.nl factor Foxn1 [9,10]. From E11.5 onwards, the first precursor T cells migrate into the thymic anlage and noncanonical NF-κB signaling becomes important for full differentiation of the medullary microenvironment, culminating in the upregulation of autoimmune regulator (Aire) [11][12][13] that enables medullary TECs to express self-antigens [2,3]. In the adult thymus cross-talk remains important, as the process of differentiation but also maintenance of medullary TECs, via ligation of RANK and CD40 by ligands expressed on thymocytes [11,12,14].Mature cortical and medullary TEC originate from a common thymic epithelial progenitor cell (TEPC) [15,16]. Although full differentiation of mature TECs from a clonal precursor population has been demonstrated, the precise phenotypical characterization of that precursor...

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Section: Lgr5 Marks a Subset Of Fetal Tecs In Early Thymus Developmentsupporting

confidence: 85%

Characterization of Lgr5‐positive epithelial cells in the murine thymus

et al. 2013

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“…Thymus fate is specified in 3rd pp endoderm as early as E9.5-10.5 prior to expression of Foxn1, which is essential for TEC differentiation and proliferation (reviewed by Manley and Condie, 2010;Gordon and Manley, 2011). Therefore, Foxn1…”

Section: Foxn1mentioning

confidence: 99%

Ectopic TBX1 suppresses thymic epithelial cell differentiation and proliferation during thymus organogenesis

et al. 2014

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The thymus and parathyroid glands arise from a shared endodermal primordium in the third pharyngeal pouch (3rd pp). Thymus fate is specified in the ventral 3rd pp between E9.5 and E11, whereas parathyroid fate is specified in the dorsal domain. The molecular mechanisms that specify fate and regulate thymus and parathyroid development are not fully delineated. Previous reports suggested that Tbx1 is required for thymus organogenesis because loss of Tbx1 in individuals with DiGeorge syndrome and in experimental Tbx1 deletion mutants is associated with thymus aplasia or hypoplasia. However, the thymus phenotype is likely to be secondary to defects in pharyngeal pouch formation. Furthermore, the absence of Tbx1 expression in the thymus-fated domain of the wild-type 3rd pp suggested that Tbx1 is instead a negative regulator of thymus organogenesis. To test this hypothesis, we generated a novel mouse strain in which expression of a conditional Tbx1 allele was ectopically activated in the thymus-fated domain of the 3rd pp. Ectopic Tbx1 expression severely repressed expression of Foxn1, a transcription factor that marks the thymus-fated domain and is required for differentiation and proliferation of thymic epithelial cell (TEC) progenitors. By contrast, ectopic Tbx1 did not alter the expression pattern of Gcm2, a transcription factor restricted to the parathyroidfated domain and required for parathyroid development. Ectopic Tbx1 expression impaired TEC proliferation and arrested TEC differentiation at an early progenitor stage. The results support the hypothesis that Tbx1 negatively regulates TEC growth and differentiation, and that extinction of Tbx1 expression in 3rd pp endoderm is a prerequisite for thymus organogenesis.

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“…The three-dimensional thymic epithelial reticulum develops from the third and fourth branchial pouch endoderm (Farley et al 2013;Gill et al 2003;Gordon and Manley 2011;Le Douarin 1967;Le Douarin et al 1984;Neves et al 2012;Rodewald 2008;Venzke 1952) and differentiates into cortical and medullary epithelial cells. Le Douarin (1967) isolated the branchial pouch endoderm, before fusion with the ectoderm of the branchial groove and co-cultured it with the mesenchyme; this resulted in the formation of functional thymic tissue providing evidence that (1) branchial endoderm without ectoderm was capable of thymic organogenesis and (2) thymic epithelial cell (TEC) differentiation required mesenchymal cell cooperation.…”

Section: Introductionmentioning

confidence: 99%

A novel aspect of the structure of the avian thymic medulla

et al. 2014

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We provide evidence for the compartmentalization of the avian thymic medulla and identify the avian thymic dendritic cell. The thymic anlage develops from an epithelial cord of the branchial endoderm. Branches of the cord are separated by primary septae of neural crest origin. The dilation of the primary septae produces the keratin-negative area (KNA) of the thymic medulla and fills the gaps of the keratin-positive network (KPN). Morphometric analysis indicates that the KNA takes up about half of the volume of the thymic medulla, which has reticular connective tissue, like peripheral lymphoid organs. The KNA receives blood vessels and in addition to pericytes, the myoid cells of striated muscle structure occupy this area. The myoid cells are of branchial arch or prechordal plate origin providing indirect evidence for the neural crest origin of the KNA. The marginal epithelial cells of the KPN co-express keratin and vimentin intermediate filaments, which indicate their functional peculiarity. The basal lamina of the primary septum is discontinuous on the surface of the KPN providing histological evidence for the loss of the blood-thymus barrier in the medulla. In the center of the KNA, the dendritic cells lie in close association with blood vessels, whereas the B-cells accumulate along the KPN. The organization of the KPN and KNA increases the "surface" of the so-called cortico-medullary border, thereby contributing to the efficacy of central tolerance.

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Mechanisms of thymus organogenesis and morphogenesis

Cited by 248 publications

References 120 publications

Characterization of Lgr5‐positive epithelial cells in the murine thymus

Characterization of Lgr5‐positive epithelial cells in the murine thymus

Ectopic TBX1 suppresses thymic epithelial cell differentiation and proliferation during thymus organogenesis

A novel aspect of the structure of the avian thymic medulla

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