T Cell Development Critically Depends on Prethymic Stromal Patched Expression

Uhmann, Anja; Brandt, Jens van den; Dittmann, Kai; Heß, Ina; Dressel, Ralf; Binder, Claudia R.; Lühder, Fred; Christiansen, Hans; Fassnacht, Martin; Bhandoola, Avinash; Wienands, Jürgen; Reichardt, Holger M.; Hahn, Heidi

doi:10.4049/jimmunol.1001939

Cited by 16 publications

(34 citation statements)

References 30 publications

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“…In contrast, other work showed that the Hh signal transducer Gli1 is not needed to mediate the effects of Hh signaling at early stages of thymocyte differentiation (86), and gain-and loss-of-function genetic models of Smoothened show that it is not required for adult BM HSC self-renewal or differentiation or for thymocyte development (87). Although previous results for Ptc deletion in hematopoietic cells suggested a role in T cell development (82), subsequent experiments showed that it is dispensable for T cell development (88); the previously observed developmental block, resulting in a reduced number of ETPs (82), could be due to a defect in thymichoming progenitors (88).…”

Section: Hh-signaling Pathwaymentioning

confidence: 93%

An Overview of the Intrathymic Intricacies of T Cell Development

Shah

Zúñiga‐Pflücker

2014

The Journal of Immunology

194

157

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The generation of a functional and diverse repertoire of T cells occurs in the thymus from precursors arriving from the bone marrow. In this article, we introduce the various stages of mouse thymocyte development and highlight recent work using various in vivo, and, where appropriate, in vitro models of T cell development that led to discoveries in the regulation afforded by transcription factors and receptor–ligand signaling pathways in specifying, maintaining, and promoting the T cell lineage and the production of T cells. This review also discusses the role of the thymic microenvironment in providing a niche for the successful development of T cells. In particular, we focus on advances in Notch signaling and developments in Notch ligand interactions in this process.

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Section: Hh-signaling Pathwaymentioning

confidence: 93%

An Overview of the Intrathymic Intricacies of T Cell Development

Shah

Zúñiga‐Pflücker

2014

The Journal of Immunology

194

157

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“…50 Uhmann et al studied a Ptch1 conditional deletion murine model and demonstrated that knockout of Ptch1 led to profound loss of mature T and B cells. 53,54 Siggins et al demonstrated that Ptch1 deletion led to significant apoptosis in pre-B cells, blocked T-cell specification in bone marrow T cells, and caused apoptosis of CD4 ϩ CD8 ϩ T cells because of deletion of Ptch1 in the supporting microenvironment. 45,54 Overall, it appears that Hh signaling has effects on the hematopoietic system dependent on developmental stage and cell lineage.…”

Section: Hh Signaling and Hematopoiesismentioning

confidence: 99%

“…53,54 Siggins et al demonstrated that Ptch1 deletion led to significant apoptosis in pre-B cells, blocked T-cell specification in bone marrow T cells, and caused apoptosis of CD4 ϩ CD8 ϩ T cells because of deletion of Ptch1 in the supporting microenvironment. 45,54 Overall, it appears that Hh signaling has effects on the hematopoietic system dependent on developmental stage and cell lineage. These effects are the result of a complex interplay between the cells and their microenvironment at certain developmental stages rather than being purely hematopoietic cell-intrinsic mechanisms.…”

Section: Hh Signaling and Hematopoiesismentioning

confidence: 99%

“…Hh signaling is critical for normal B-and T-cell development; however, it is primarily the microenvironmental cells and supportive stroma of the bone marrow and lymphoid organs that produce the HH ligand, which is required for lymphoid cell maintenance. 45,54 Constituents and targets of Hh signaling are expressed in various lymphoma cell lines and primary tissue. [92][93][94] IHH and SHH have been shown to be survival factors in B-cell malignancies.…”

Section: Lymphoma and Cllmentioning

confidence: 99%

“…49,50 Early studies suggested that Hh signaling negatively regulated T-cell development 51 ; however, subsequent work indicates that Hh signaling has a positive regulatory role in early T-cell development. 45,49,50,[52][53][54] Both IHH and SHH affect T-cell proliferation and maturation. 49,52 Conditional deletion of Smo at different levels of T-cell development, performed by El Andaloussi et al, suggested that abrogation of Smo expression mainly affects primitive thymocytes, leading to thymic atrophy and profound defects in early T-cell survival, proliferation, and maturation.…”

Section: Hh Signaling and Hematopoiesismentioning

confidence: 99%

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Targeting hedgehog in hematologic malignancy

Irvine

Copland

2012

Blood

126

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The Hedgehog pathway is a critical mediator of embryonic patterning and organ development, including hematopoiesis. It influences stem cell fate, differentiation, proliferation, and apoptosis in responsive tissues. In adult organisms, hedgehog pathway activity is required for aspects of tissue maintenance and regeneration; however, there is increasing awareness that abnormal hedgehog signaling is associated with malignancy. Hedgehog signaling is critical for early hematopoietic development, but there is controversy over its role in normal hematopoiesis in adult organisms where it may be dispensable. Conversely, hedgehog signaling appears to be an important survival and proliferation signal for a spectrum of hematologic malignancies. Furthermore, hedgehog signaling may be critical for the maintenance and expansion of leukemic stem cells and therefore provides a possible mechanism to selectively target these primitive cell subpopulations, which are resistant to conventional chemotherapy. Indeed, phase 1 clinical trials of hedgehog pathway inhibitors are currently underway to test this hypothesis in myeloid leukemias. This review covers: (1) the hedgehog pathway and its role in normal and malignant hematopoiesis, (2) the recent development of clinical grade small molecule inhibitors of the pathway, and (3) the potential utility of hedgehog pathway inhibition as a therapeutic strategy in hemato-oncology.

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Inactivation of Patched1 in Murine Chondrocytes Causes Spinal Fusion Without Inflammation

Dittmann

Wuelling

Uhmann

et al. 2014

Arthritis & Rheumatology

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Objective. During development of the vertebrate skeleton, chondrocytes form a cartilage template that is gradually replaced by bone. Hormones of the Hedgehog (HH) family have been implicated in the ossification process, but their exact relationship to normal or pathogenic bone formation is unclear. This study was undertaken to establish a genetic tool that allows the discrete inactivation of genes in spinal chondrocytes, and to investigate in vivo how chondrocyte-specific ablation of the inhibitory HH receptor Patched 1 (Ptch1) affects skeleton integrity.Methods. A Cre-deleter mouse strain, mb1-Cre, for selective gene recombination in spinal chondrocytes was identified by in situ hybridization and histologic analysis. The mb1-Cre ؉/؊ animals were crossed with mice that harbor a loxP-flanked Ptch1 gene (Ptch1 flox/flox ) to abrogate the inhibition of the HH signaling pathway in chondrocytes. The skeletal integrity of F1 mice was characterized by high-resolution flat-panel-based volume computed tomography and histologic staining procedures.Results. During the first weeks after birth, all mb1-Cre ؉/؊ /Ptch1 flox/flox mice developed progressive spinal fusion with malformation of the vertebrae. This phenotype was caused by aberrant chondrocyte proliferation in the intervertebral discs that blocked endochondral ossification. Importantly, the disease pattern occurred in an inflammation-independent manner. Conclusion.Our findings indicate that chronic activation of the HH signal pathway in spinal chondrocytes can trigger an ankylosing spine morphology without immune cell contributions. Hence, the destruction of cartilage and loss of axial joint integrity can result from chondrocyte-intrinsic defects of monogenic origin.Development of the axial and appendicular skeleton of vertebrates is initiated by local condensation of mesenchymal cells and their differentiation into chondrocytes, which form cartilage anlagen (1,2). Proper ossification of the anlagen is associated with a complex chondrocyte maturation program (3). Small, highly proliferating chondrocytes produce extracellular matrix proteins that comprise types II, IX, and XI collagen as well as the proteoglycan aggrecan.Indian hedgehog (IHH), a member of the hedgehog (HH) family of secreted morphogens, and parathyroid hormone-related protein (PTHrP) have been reported to maintain chondrocytes in a proliferative state (4-7). Other growth factors, such as thyroid hormone or bone morphogenic proteins, antagonize the actions of IHH and PTHrP, thereby promoting cell cycle exit. This is followed by terminal differentiation of chondrocytes into hypertrophic cells, which secrete type X collagen (ColX) and ultimately die by apoptosis. Following its calcification, the cartilage matrix provides a template for the balanced action of hematopoietic osteoclasts and mesenchyme-derived osteoblasts to finalize bone formation. The long bones and the vertebrae of the spinal column are connected by synovial joints and intervertebral discs, respectively.Chondrogenesis and endochondral oss...

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T Cell Development Critically Depends on Prethymic Stromal Patched Expression

Cited by 16 publications

References 30 publications

An Overview of the Intrathymic Intricacies of T Cell Development

An Overview of the Intrathymic Intricacies of T Cell Development

Targeting hedgehog in hematologic malignancy

Inactivation of Patched1 in Murine Chondrocytes Causes Spinal Fusion Without Inflammation

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