Evidence for a Functional Second Thymus in Mice

Terszowski, Grzegorz; Müller, Susanna; Bleul, Conrad C.; Blum, Carmen; Schirmbeck, Reinhold; Reimann, Jörg; Pasquier, Louis Du; Amagai, Takashi; Boehm, Thomas; Rodewald, Hans Reimer

doi:10.1126/science.1123497

Cited by 140 publications

(122 citation statements)

References 19 publications

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“…It is possible that during its descent, the rudiment may leave behind fragments in some strains, leading to the cervical thymi described before, an extreme manifestation of which are the mutants we present here (37,38). However, in mice deficient for ephrin-B2 expression on NCCs, two contralateral thymic structures were present, along with lymph nodes.…”

Section: Discussionmentioning

confidence: 57%

EphB–ephrin-B2 interactions are required for thymus migration during organogenesis

Foster¹,

Jack

Cardenas

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Thymus organogenesis requires coordinated interactions of multiple cell types, including neural crest (NC) cells, to orchestrate the formation, separation, and subsequent migration of the developing thymus from the third pharyngeal pouch to the thoracic cavity. The molecular mechanisms driving these processes are unclear; however, NC-derived mesenchyme has been shown to play an important role. Here, we show that, in the absence of ephrin-B2 expression on thymic NC-derived mesenchyme, the thymus remains in the cervical area instead of migrating into the thoracic cavity. Analysis of individual NC-derived thymic mesenchymal cells shows that, in the absence of ephrin-B2, their motility is impaired as a result of defective EphB receptor signaling. This implies a NC-derived cellspecific role of EphB-ephrin-B2 interactions in the collective migration of the thymic rudiment during organogenesis.T hymus development in the mouse begins at E9.5 with the formation of the third pharyngeal pouches and concomitant expression of transcription factors including Hoxa3, Pax1/9, Eya1, and Six1/4 within the third pharyngeal pouch endoderm (1-4). Soon after, neural crest (NC)-derived mesenchymal cells (NCCs) from the posterior hindbrain undergo epithelial-to-mesenchymal transition (EMT), delaminate, and migrate to and surround the pouch, which simultaneously begins to grow into a separate structure containing the thymus and parathyroid primordia. By E12.5, the thymic primordium is completely detached from both the pharyngeal pouch and parathyroid. Subsequently, the bilateral lobes descend into the thoracic cavity, where they finally settle in the upper mediastinum above the heart. NCCs, which contribute to various tissues in the mouse, are also key players in thymus organogenesis. NC-derived cells have been shown to regulate patterning of the third-pouch endoderm into thymus and parathyroid-specific domains (5) and stimulate thymic epithelial cell (TEC) proliferation and maturation through production of FGFs (6). NC-derived cells also stabilize blood-vessel structures by differentiating into perivascular cells (7,8).The mechanisms that control the various morphogenetic events during early thymus organogenesis are still largely unknown, although some genes have been identified that affect these events. Hox3 and Pax1/9 transcription factors act in a pathway that is required for proper separation and/or migration of the developing thymic and parathyroid primordia from the pharynx, although the cell-type specificity of these functions is poorly understood (2, 9, 10). Splotch embryos, which have a null allele of Pax3 and are largely deficient of NCCs, also exhibit pharyngeal-pouch defects, including an ectopic thymus (5, 11). This NCC deficiency resulted in delayed separation of the thymus and parathyroid from the pharynx, and the boundary between thymus and parathyroid-fated domains was abnormal. These results strongly implicated NCC migration to the third pharyngeal pouch in patterning and morphogenesis of the thymus and parathyroids (5...

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Section: Discussionmentioning

confidence: 57%

EphB–ephrin-B2 interactions are required for thymus migration during organogenesis

Foster¹,

Jack

Cardenas

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Using thymectomy procedures, we were unable to identify a role for p21 in T cell survival (30,35). However, such experiments are limited because recent reports have indicated the presence of more than one functional thymus in mice (47). Transfer of the various YF series of mice into appropriate MHC-deficient hosts that express or lack the selecting allele could be another way in which to address this question.…”

Section: Discussionmentioning

confidence: 97%

The Constitutive Tyrosine Phosphorylation of CD3ζ Results from TCR-MHC Interactions That Are Independent of Thymic Selection

Becker

DeFord-Watts

Wuelfing

et al. 2007

The Journal of Immunology

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The TCR complex, when isolated from thymocytes and peripheral T cells, contains a constitutively tyrosine-phosphorylated CD3ζ molecule termed p21. Previous investigations have shown that the constitutive phosphorylation of CD3ζ results from TCR interactions with MHC molecules occurring in both the thymus and the periphery. To determine what contribution the selection environment had on this constitutive phosphorylation, we analyzed CD3ζ from several distinct class I- and II-restricted TCR-transgenic mice where thymocyte development occurred in either a selecting or a nonselecting MHC environment. Herein, we report that constitutively phosphorylated CD3ζ (p21) was present in thymocytes that developed under nonselecting peptide-MHC conditions. These findings strongly support the model that the TCR has an inherent avidity for MHC molecules before repertoire selection. Biochemical analyses of the TCR complex before and after TCR stimulation suggested that the constitutively phosphorylated CD3ζ subunit did not contribute to de novo TCR signals. These findings may have important implications for T cell functions during self-MHC recognition under normal and autoimmune circumstances.

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“…We therefore examined this strain of mice using RANKL and M-CSF-derived osteoclasts, which behaved in a manner similar to the Balb/c-derived cells reported here (data not shown). Different mouse vendors could also be contributing to differences, a possibility that is strengthened by the observation of variability in mouse colonies between vendors [46]. The approach to assess apoptosis also differed in that Hughes et al observed that apoptotic osteoclasts lifted off of the culture surface and chromatin condensation of floating cells was used as the apoptosis marker.…”

Section: Discussionmentioning

confidence: 99%

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

Gingery

Bradley

Pederson

et al. 2008

Experimental Cell Research

162

120

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To better understand the roles of TGF-β in bone metabolism, we investigated osteoclast survival in response TGF-β and found that TGF-β inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-β receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-β treatment. Since osteoclast survival involves MEK, AKT, and NFκB activation, we examined TGF-β effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IκB, and NFκB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFκB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFκB repressed TGF-β-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-β-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclX L expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-β-induced NFκB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-β to support of osteoclast survival.

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Evidence for a Functional Second Thymus in Mice

Cited by 140 publications

References 19 publications

EphB–ephrin-B2 interactions are required for thymus migration during organogenesis

EphB–ephrin-B2 interactions are required for thymus migration during organogenesis

The Constitutive Tyrosine Phosphorylation of CD3ζ Results from TCR-MHC Interactions That Are Independent of Thymic Selection

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

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