YAP/TAZ direct commitment and maturation of lymph node fibroblastic reticular cells

Choi, Sung Yong; Bae, Hosung; Jeong, Sunhye; Park, Intae; Cho, Hyunsoo; Hong, Seon Pyo; Lee, Da-Hye; Lee, Choong-kun; Park, Jin-Sung; Suh, Sang Heon; Choi, Jeongwoon; Yang, Myung Jin; Jang, Jeon Yeob; Onder, Lucas; Moon, Jeong Hwan; Jeong, Han‐Sin; Adams, Ralf H.; Kim, Jin Man; Ludewig, Burkhard; Song, Joo‐Hye; Lim, Dae‐Sik; Koh, Gou Young

doi:10.1038/s41467-020-14293-1

Cited by 37 publications

(61 citation statements)

References 53 publications

(72 reference statements)

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“…Inhibition of dysregulated TAZ expression in arthritic patient induces Treg cell-mediated anti-inflammatory effect (Du et al 2020 ). TAZ also regulates lymph node differentiation, in particular, commitment and maturation of fibroblastic reticular cells (Choi et al 2020 ). The fine-tuning of TAZ expression and its activity is essential for maintaining normal tissue homeostasis and limiting cancer incidence.…”

Section: Introductionmentioning

confidence: 99%

The essential role of TAZ in normal tissue homeostasis

2021

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Transcriptional coactivator with PDZ-binding motif (TAZ) has been extensively characterized in organ development, tissue regeneration, and tumor progression. In particular, TAZ functions as a Hippo mediator that regulates organ size, tumor growth and migration. It is highly expressed in various types of human cancer, and has been reported to be associated with tumor metastasis and poor outcomes in cancer patients, suggesting that TAZ is an oncogenic regulator. Yes-associated protein (YAP) has 60% similarity in amino acid sequence to TAZ and plays redundant roles with TAZ in the regulation of cell proliferation and migration of cancer cells. Therefore, TAZ and YAP, which are encoded by paralogous genes, are referred to as TAZ/YAP and are suggested to be functionally equivalent. Despite its similarity to YAP, TAZ can be clearly distinguished from YAP based on its genetic, structural, and functional aspects. In addition, targeting superabundant TAZ can be a promising therapeutic strategy for cancer treatment; however, persistent TAZ inactivation may cause failure of tissue homeostatic control. This review focuses primarily on TAZ, not YAP, discusses its structural features and physiological functions in the regulation of tissue homeostasis, and provides new insights into the drug development targeting TAZ to control reproductive and musculoskeletal disorders.

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Section: Introductionmentioning

confidence: 99%

The essential role of TAZ in normal tissue homeostasis

2021

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“… mmu-miR-7019-3p, mmu-miR-3080-5p, mmu-miR-1952, mmu-miR-7008-5p, mmu-miR-6935-5p, mmu-miR-6922-5p, mmu-miR-1249-3p, mmu-miR-219b-5p, mmu-miR-3099-5p, mmu-miR-7038-3p, mmu-miR-705, mmu-miR-6993-5p DsRed.T3 transgenic mice (stock No. 005441) [ 9 ] Dcx-DsRed transgenic mice (stock No. 009655) [ 42 ] NG2DsRedBAC transgenic mice (stock No.…”

Section: Resultsmentioning

confidence: 99%

“…Because all three intronic sequences do not include any known miRNAs or predicted stem-loop structures, they seem to act in trans as long ncRNA regulatory elements [20]. Similarly, constructs containing common selection markers/reporter genes like GFP, EGFP, Neo r , LacZ, and DsRed are often left within the target genome postselection [9,21,29,37,62]. However, these genes themselves can become potential targets of miRNAs of host origin, e.g., Mus musculus as discussed later.…”

Section: The Problemmentioning

confidence: 99%

Inadvertent nucleotide sequence alterations during mutagenesis: highlighting the vulnerabilities in mouse transgenic technology

Ghosh

Chakrabarti

Shukla

2021

Journal of Genetic Engineering and Biotechnology

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In the last three decades, researchers have utilized genome engineering to alter the DNA sequence in the living cells of a plethora of organisms, ranging from plants, fishes, mice, to even humans. This has been conventionally achieved by using methodologies such as single nucleotide insertion/deletion in coding sequences, exon(s) deletion, mutations in the promoter region, introducing stop codon for protein truncation, and addition of foreign DNA for functional elucidation of genes. However, recent years have witnessed the advent of novel techniques that use programmable site-specific nucleases like CRISPR/Cas9, TALENs, ZFNs, Cre/loxP system, and gene trapping. These have revolutionized the field of experimental transgenesis as well as contributed to the existing knowledge base of classical genetics and gene mapping. Yet there are certain experimental/technological barriers that we have been unable to cross while creating genetically modified organisms. Firstly, while interfering with coding strands, we inadvertently change introns, antisense strands, and other non-coding elements of the gene and genome that play integral roles in the determination of cellular phenotype. These unintended modifications become critical because introns and other non-coding elements, although traditionally regarded as “junk DNA,” have been found to play a major regulatory role in genetic pathways of several crucial cellular processes, development, homeostasis, and diseases. Secondly, post-insertion of transgene, non-coding RNAs are generated by host organism against the inserted foreign DNA or from the inserted transgene/construct against the host genes. The potential contribution of these non-coding RNAs to the resulting phenotype has not been considered. We aim to draw attention to these inherent flaws in the transgenic technology being employed to generate mutant mice and other model organisms. By overlooking these aspects of the whole gene and genetic makeup, perhaps our current understanding of gene function remains incomplete. Thus, it becomes important that, while using genetic engineering techniques to generate a mutant organism for a particular gene, we should carefully consider all the possible elements that may play a potential role in the resulting phenotype. This perspective highlights the commonly used mouse strains and the most probable associated complexities that have not been considered previously, resulting in possible limitations in the currently utilized transgenic technology. This work also warrants the use of already established mouse lines in further research.

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“…Focusing on the signaling pathway(s) driving FRC actomyosin contractility, we provide evidence that the spontaneous contractility of quiescent FRC relies on a basal level of YAP and JAK1-STAT3 activation, and not only on the PDPN-ERM pathway as previously identified in murine FRC. YAP activation was known to reflect the actomyosin contractile state of FRC (20) and CAF (27), and to regulate FRC differentiation during LN development (47). We show here that YAP is not only a marker but also controls actomyosin contractility of differentiated human FRC.…”

Section: Discussionmentioning

confidence: 99%

Invasive dedifferentiated melanoma cells inhibit JAK1-STAT3-driven actomyosin contractility of human fibroblastic reticular cells of the lymph node

Rovera

Berestjuk

Lecacheur

et al. 2021

Preprint

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Fibroblastic reticular cells (FRC) are immunologically specialized fibroblasts controlling the size and microarchitecture of the lymph node (LN), partly through their contractile properties. Swelling is a hallmark of tumor-draining LN in lymphophilic cancers such as cutaneous melanoma, a very aggressive and heterogeneous tumor with high risk of early metastasis. Melanoma cells can dynamically switch between melanocytic proliferative and dedifferentiated mesenchymal-like invasive phenotypes, which are characterized by distinct transcriptional signatures. Melanoma secreted cues, such as extracellular vesicles, growth factors or proinflammatory cytokines, promote LN stroma remodeling and metastatic spreading. But how FRC integrate these pro-metastatic signals and modulate their contractile functions remains poorly characterized. Here, we show that factors secreted by dedifferentiated melanoma cells, but not by melanocytic cells, strongly inhibit FRC actomyosin-dependent contractile forces by decreasing the activity of the RHOA-ROCK pathway and the mechano-responsive transcriptional co-activator YAP, leading to a decrease in F-actin stress fibers and cell elongation. Transcriptional profiling and biochemical analyses indicate that FRC actomyosin cytoskeleton relaxation is driven by inhibition of JAK1 and its downstream transcription factor STAT3, and is associated with increased FRC proliferation and activation. Interestingly, dedifferentiated melanoma cells reduce FRC contractility in vitro independently of extracellular vesicle secretion. These data show that FRC are specifically modulated by proteins secreted by invasive dedifferentiated melanoma cells and suggest that melanoma-derived cues could modulate the biomechanical properties of distant LN before metastatic invasion. They also highlight that JAK1- STAT3 and YAP signaling pathways contribute to the maintenance of the spontaneous contractility of resting human FRC.

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YAP/TAZ direct commitment and maturation of lymph node fibroblastic reticular cells

Cited by 37 publications

References 53 publications

The essential role of TAZ in normal tissue homeostasis

The essential role of TAZ in normal tissue homeostasis

Inadvertent nucleotide sequence alterations during mutagenesis: highlighting the vulnerabilities in mouse transgenic technology

Invasive dedifferentiated melanoma cells inhibit JAK1-STAT3-driven actomyosin contractility of human fibroblastic reticular cells of the lymph node

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