Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution

O’Neill, Kathy E.; Bredenkamp, Nicholas; Tischner, Christin; Vaidya, Harsh Jayesh; Stenhouse, Frances H.; Peddie, C. Diana; Nowell, Craig S.; Gaskell, Terri; Blackburn, C. Clare

doi:10.1371/journal.pone.0151666

Cited by 42 publications

(43 citation statements)

References 29 publications

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“…However, published microarray data suggest Bmp4 levels may be reduced between 1 and 3 months of age . Collectively, these data further narrow the recently proposed time window of Foxn1 down regulation associated with thymic involution . Furthermore, Bmpr2 expression was predominantly found in the cTEC lo subset, which corroborates our TEPC phenotype .…”

Section: Discussionsupporting

confidence: 86%

A novel Foxn1^eGFP/+ mouse model identifies Bmp4‐induced maintenance of Foxn1 expression and thymic epithelial progenitor populations

et al. 2016

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Although forkhead-box n1 (Foxn1) is a critical thymic epithelial cell regulator in thymus organogenesis, its association with epithelial differentiation and homeostasis in the postnatal and aged thymic microenvironment remains conflicting. Consequently, we have generated a Foxn1 knock-in mouse model that allows for refined investigation of the aging thymic epithelium. This reporter line differs from those previously published in that concomitant expression of enhanced green fluorescent protein enables live cell sorting of Foxn1 cell populations. Our heterozygotes did not exhibit haploinsufficiency, with Foxn1 expression resembling that of wild-type mice. Comparative analysis between Foxn1 and enhanced green fluorescent protein at both the transcriptional and translational levels revealed co-localization, with progressive down-regulation observed predominantly in the aging cortical epithelium. Supplementation with bone morphogenetic protein (Bmp)-4 enhanced Foxn1 expression and colony forming efficiency in both embryonic and adult progenitor 3D cultures. Strikingly, selective maintenance of immature cortical and medullary epithelial cells was observed which is consistent with the higher Bmp receptor 2 expression levels seen in these progenitor populations. This study demonstrates the significance of our mouse model in unraveling the role of this master regulator in thymus development, homeostasis and aging, providing a faithful reporter system for phenotypic and functional investigations.

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Section: Discussionsupporting

confidence: 86%

A novel Foxn1^eGFP/+ mouse model identifies Bmp4‐induced maintenance of Foxn1 expression and thymic epithelial progenitor populations

et al. 2016

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“…Foxn1 expression is restricted to epithelial cells, both in the skin and in the thymus . In the thymus, a comprehensive analysis showed that the progressive decline of Foxn1 expression is associated with age‐related degeneration of the thymus . Our analysis of skin tissues confirmed Foxn1 localization to epithelial cells, particularly the suprabasal layer of epidermis, and to hair follicles, regardless of the animal's age .…”

Section: Discussionsupporting

confidence: 59%

“…9,14,18 In the thymus, a comprehensive analysis showed that the progressive decline of Foxn1 expression is associated with age-related degeneration of the thymus. 19,20 Our analysis of skin tissues confirmed Foxn1 localization to epithelial cells, particularly the suprabasal layer of epidermis, and to hair follicles, regardless of the animal's age. 21 However, in contrast to the thymus, measurements of Foxn1 mRNA expression levels by qRT-PCR analysis in uninjured epidermis samples did not show expected decline with animal age.…”

Section: Discussionsupporting

confidence: 54%

“…Well documented data of the age related decrease in Foxn1 expression in the thymus epithelium, which correlates with thymus involution, spurred our study toward possible age‐related changes in skin Foxn1 expression. However, neither gene expression data nor flow cytometric analysis of Foxn1‐eGFP positive cells detected an age related decrease in Foxn1 expression in intact skin or differences in Foxn1 modulation during the skin wound healing process in adult vs. old animals.…”

Section: Discussionmentioning

confidence: 94%

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Foxn1 and Mmp‐9 expression in intact skin and during excisional wound repair in young, adult, and old C57Bl/6 mice

Kopcewicz

Kur‐Piotrowska

Bukowska

et al. 2017

Wound Repair Regeneration

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The transcription factor Foxn1 is essential for skin development. Our previous studies performed on young C57BL/6J mice model showed that Foxn1 acts as regulator of the skin wound healing process. The present study extended our initial research regarding the expression and potential role of Foxn1 in the intact and wounded skin as a function of animal age and stage of the wound healing process. We analyzed Foxn1 and Mmp-9 expression in the intact and postinjured skin of young, adult, and old C57BL/6J and transgenic Foxn1::Egfp mice. The similar levels of epidermal Foxn1 mRNA expression were detected in young and adult C57BL/6J mice and higher levels in old animals. Postinjured skin tissues displayed a gradual decrease of Foxn1 mRNA expression at Days 1, 5, and 7 after injury. Foxn1-eGFP positive cells were abundant at wound margin and in re-epithelialized epidermis at postwounded Days 1, 5, and 7 and colocalized with E-cadherin and Mmp-9. Postwounded skin at Days 14-36 displayed Foxn1-eGFP cells in the epidermis and in the dermal part of the skin (papillary dermis). A subset of Foxn1-eGFP positive cells in the papillary dermis expressed the myofibroblast marker αSMA. Flow cytometric analysis of cells isolated from postwounded (Day 7) skin tissues showed a significant increase in the percentage of Foxn1-eGFP positive cells with phenotype of double positivity for E-cadherin/N-cadherin (epithelial/mesenchymal markers). Collectively, these data identify the transcription factor Foxn1 as a potential key epidermal regulator modifying both epidermal and dermal healing processes after cutaneous wounding.

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“…The second phase of thymic involution occurs during the process of organism aging and is manifested as a gradual reduction of thymic size and naïve T cell production. Foxn1 reduction in TECs soon after birth appears to contribute to the first developmental phase of thymic involution (L. Chen, Xiao, & Manley, 2009; O’Neill et al, 2016; Rode et al, 2015), but the cause of the second and age-associated phase of involution is unknown.…”

Section: Introductionmentioning

confidence: 99%

Cell type-specific role of lamin-B1 and its inflammation-driven reduction in organ building and aging

Zheng

2018

Preprint

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Cellular architectural proteins often participate in organ development and maintenance.Although functional decay of some of these proteins during aging is known, the cell-type specific developmental role and the cause and consequence of their subsequent decay remain to be established especially in mammals. By studying lamins, the nuclear structural proteins, we demonstrate that lamin-B1 functions specifically in the thymic epithelial cells (TECs) for proper thymus organogenesis. An upregulation of proinflammatory cytokines in the intra-thymic myeloid immune cells during aging accompanies a gradual reduction of adult TEC lamins-B1.These cytokines cause adult TEC senescence and lamin-B1 reduction. We identify 17 adult TEC subsets and show that TEC lamin-B1 maintains the composition of these TECs. Lamin-B1 supports the expression of TEC genes needed for maintaining adult thymic architecture and function. Thus, structural proteins involved in organ building and maintenance can undergo inflammation-driven decay which can in turn contribute to age-associated organ degeneration. mTECs. We mixed an adherent keratin-negative cell line (RAW264.7 from ATCC #TIB-71) applying FACS to isolate macrophages in thymuses dissected from 2, 6, 12, 16, and 20-mon-old 0 Chromium and then single-cell RNA-seq libraries were generated using the Chromium Single Cell 3' Reagent Kit (10X Genomics) by the core facility at the Embryology Department of Carnegie Institute for Science. Briefly, TEC single-cell suspension (~1,000 cells per 1 µl PBS) was mixed thoroughly with Single Cell 3' gel beads and partitioning oil into a Single Cell 3' Chip (10X genomics) following the recommended protocol for the Chromium Single Cell 3' Reagent Kit (v2 Chemistry). RNA transcripts of single cells were uniquely barcoded and reversetranscribed within the individual droplets. cDNA molecules were then pre-amplified and pooled together followed by the final library construction. Libraries were sequenced by paired-end 150bp reads on Illumina NextSeq500. Post-processing and quality control were performed by the same genomics core facility using the 10X Cell Ranger package (V2.

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Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution

Cited by 42 publications

References 29 publications

A novel Foxn1^eGFP/+ mouse model identifies Bmp4‐induced maintenance of Foxn1 expression and thymic epithelial progenitor populations

A novel Foxn1^eGFP/+ mouse model identifies Bmp4‐induced maintenance of Foxn1 expression and thymic epithelial progenitor populations

Foxn1 and Mmp‐9 expression in intact skin and during excisional wound repair in young, adult, and old C57Bl/6 mice

Cell type-specific role of lamin-B1 and its inflammation-driven reduction in organ building and aging

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Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution

Cited by 42 publications

References 29 publications

A novel Foxn1eGFP/+ mouse model identifies Bmp4‐induced maintenance of Foxn1 expression and thymic epithelial progenitor populations

A novel Foxn1eGFP/+ mouse model identifies Bmp4‐induced maintenance of Foxn1 expression and thymic epithelial progenitor populations

Foxn1 and Mmp‐9 expression in intact skin and during excisional wound repair in young, adult, and old C57Bl/6 mice

Cell type-specific role of lamin-B1 and its inflammation-driven reduction in organ building and aging

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A novel Foxn1^eGFP/+ mouse model identifies Bmp4‐induced maintenance of Foxn1 expression and thymic epithelial progenitor populations

A novel Foxn1^eGFP/+ mouse model identifies Bmp4‐induced maintenance of Foxn1 expression and thymic epithelial progenitor populations