NFS/N-nu/+ Mice Can Macroscopically Be Distinguished from NFS/N-+/+ Littermates by Their Thymic Size and Shape

Kojima, Akinori; Saito, Muneo; Hioki, Kyoji; Shimanura, Kazuo; Habu, Sonoko

doi:10.1159/000163242

Cited by 9 publications

(10 citation statements)

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“…Mild haploinsufficiency has been reported in Foxn1 nu/+ heterozygotes, with researchers observing altered thymic size and shape [33], thymocyte-induced reduction in thymic weight [34], and mild stromal disorganization and thymocyte developmental defects [19]. Additionally, in the Foxn1 LacZ mouse, postnatal down-regulation of Foxn1 caused thymic stromal degeneration and diminished T cell production in a dosage-sensitive manner, characteristic of age-associated atrophy [19].…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…It has been known for more than 3 decades that the ϩ/nu thymus has a mild thymus size reduction, 41,42 indicating that Foxn1 dose is critical for thymus development. Our data show that 50% of normal Foxn1 expression (ϩ/nu) caused reduced thymus size and thymocyte production and mild stromal organization and thymocyte development defects.…”

Section: Discussionmentioning

confidence: 99%

Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner

Chen

Xiao

Manley

2009

Blood

193

264

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The postnatal thymus is the primary source of T cells in vertebrates, and many if not all stages of thymocyte development require interactions with thymic epithelial cells (TECs). The Foxn1 gene is a key regulator of TEC differentiation, and is required for multiple aspects of fetal TEC differentiation. Foxn1 is also expressed in the postnatal thymus, but its function after birth is unknown. We generated a Foxn1 allele with normal fetal expression and thymus development, but decreased expression in the postnatal thymus. This down-regulation causes rapid thymic compartment degeneration and reduced T-cell production. TEC subsets that express higher Foxn1 levels are most sensitive to its down-regulation, in particular MHCII hi UEA-1 hi medullary TECs. The requirement for Foxn1 is extremely dosage sensitive, with small changes in Foxn1 levels having large effects on thymus phenotypes. Our results provide the first evidence that Foxn1 is required to maintain the postnatal thymus. Furthermore, the similarities of this phenotype to accelerated aging-related thymic involution support the possibility that changes in Foxn1 expression in TECs during aging contribute to the mechanism of involution. (Blood. 2009;113:567-574) IntroductionThe postnatal thymus consists of a complex cellular and extracellular environment through which developing thymocytes migrate in a stereotypical manner during their differentiation to self-restricted, self-tolerant T cells. 1,2 The principal thymic stromal cell types are thymic epithelial cells (TECs), which are broadly divided into cortical and medullary classes, and have specific functions to promote all stages of thymocyte development. 3,4 The normal postnatal thymus displays dramatic shifts in size and phenotype over the life of the animal due to the influence of external and internal changes. In the early postnatal stage the thymus undergoes rapid logarithmic expansion in size and T-cell production, and the stroma becomes organized and expanded. At about 1 to 2 weeks (in mice), the thymus enters a period of relative homeostasis and high thymic output that continues until early adulthood. This period results in the generation of a normal complement of peripheral T cells with a diverse repertoire. After this point, the thymus gradually undergoes a process known as age-associated involution. The fully involuted thymus has significantly reduced thymopoiesis. The thymic architecture is changed, as TEC numbers decrease and the cortical and medullary compartments break down. 5 Besides a dramatic decrease in the production of naive T cells, the percentage of the most immature (DN1) thymocyte subpopulation is increased in aged mice, 6,7 although the number of early thymic progenitors (ETPs) is decreased. 8,9 Both the initial development and the maintenance of thymic compartment organization and T-cell production require ongoing productive interactions between thymocytes and thymic stromal cells. 10 Failure to maintain the postnatal thymus results in dramatically reduced T-cell production, and thu...

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“…Young ϩ/nu heterozygous mice have mildly reduced thymic size (54,55) and may have premature TEC dysfunction in the fetal and postnatal stage due to the presence of one copy of FoxN1 carrying a germ line null mutation. This would make it difficult to determine whether TEC changes result from induced postnatal loss of FoxN1 or from prenatal haploinsufficiency.…”

Section: K8mentioning

confidence: 99%

Postnatal Tissue-specific Disruption of Transcription Factor FoxN1 Triggers Acute Thymic Atrophy

Cheng

Guo

Sun

et al. 2010

Journal of Biological Chemistry

143

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The transcription factor FoxN1 is essential for differentiation of thymic epithelial cell (TEC) progenitors during thymic organogenesis. However, limited information is available on the postnatal contribution of FoxN1 to thymic maintenance. To address this question, we generated a loxP-floxed FoxN1 (fx) mouse with three different promoter-driven inducible CreER T transgenes. Postnatal ubiquitous deletion of FoxN1 caused dramatic thymic atrophy in 5 days and more severe deterioration in medullary TECs (mTECs) than in cortical TECs (cTECs). Induction of FoxN1 deletion selectively in K5 promoter-driven somatic epithelial cells (mostly mTECs and possibly some adult epithelial stem cells) was sufficient to cause significant thymic atrophy, whereas FoxN1 deletion in K18 promoter-driven somatic epithelial cells (mostly cTECs) was not. Thymic atrophy resulted from increased apoptosis and was associated with activation of the p53 gene in mature mTECs. Although FoxN1 is required for the development of both mTECs and cTECs in thymic organogenesis, it is most important for the maintenance of mTECs in the postnatal thymus, which are in turn necessary to prevent thymic atrophy.The thymus gland is not only required for ontogenesis but is also indispensable for postnatal cellular immune system function (1) through replenishment of the naive T-cell pool and maintenance of diversity of the T-cell receptor repertoire, establishment of central immune tolerance by depleting selfreactive T-cell clones, and generation of natural regulatory T cells to maintain immune balance (2, 3). Many intrinsic and extrinsic factors can induce atrophy of the mature thymus and disrupt thymic functions (4, 5). Thymic atrophy is generally believed to result from deterioration of the interactions between lymphohematopoietic progenitor cells and nonhematopoietic thymic stromal cells (TSCs), 3 primarily thymic epithelial cells (TECs) in the thymus (6, 7). Therefore, changes in expression of genes and transcription factors, related to lymphohematopoietic progenitor cell and/or TEC functions may regulate thymic involution.FoxN1 is an epithelial cell-autonomous gene that encodes a forkhead-box transcription factor related to the immune system (8) and skin epithelial cells (9). FOXN1 in humans and FoxN1 in rodents are highly conserved in their sequence and function. A mutation in FoxN1 generates alymphoid cystic thymic dysgenesis due to defective TECs (10, 11), causing primary T-cell immunodeficiency (12-15), and leads to a hairless "nude" phenotype (9). TECs have two major subsets, medullary and cortical TECs (mTEC and cTEC), based on anatomic regions, expressed molecules, and function. mTECs mediate negative selection of T cells and control the maturation of T cells prior to leaving the thymus, whereas cTECs foster the development of CD4 Ϫ 8 Ϫ T-cell progenitors and regulate positive selection of T cells. Both mTECs and cTECs are FoxN1-dependent (16) during fetal thymic organogenesis, as demonstrated in mouse models (11,17,18). However, it is unclear whethe...

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NFS/N-nu/+ Mice Can Macroscopically Be Distinguished from NFS/N-+/+ Littermates by Their Thymic Size and Shape

Cited by 9 publications

References 1 publication

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 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner

Postnatal Tissue-specific Disruption of Transcription Factor FoxN1 Triggers Acute Thymic Atrophy

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NFS/N-nu/+ Mice Can Macroscopically Be Distinguished from NFS/N-+/+ Littermates by Their Thymic Size and Shape

Cited by 9 publications

References 1 publication

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 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner

Postnatal Tissue-specific Disruption of Transcription Factor FoxN1 Triggers Acute Thymic Atrophy

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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