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

Marco Barsanti, Joanna M. C. Lim, Michael L. Hun, Natalie Lister, Kahlia Wong, Maree V. Hammett, Ailin Lepletier, Richard L. Boyd, Antonietta Giudice, Ann P. Chidgey

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 Foxn1eGFP/+ 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.
Original languageEnglish
Pages (from-to)291-304
Number of pages14
JournalEuropean Journal of Immunology
Volume47
Issue number2
DOIs
Publication statusPublished - Feb 2017

Keywords

  • thymic epithelial progenitor cell
  • thymic epithelial cell
  • Foxn1
  • Bmp4
  • Foxn1dGFP mouse model
  • thymus development
  • aging

Cite this

Barsanti, Marco ; Lim, Joanna M. C. ; Hun, Michael L. ; Lister, Natalie ; Wong, Kahlia ; Hammett, Maree V. ; Lepletier, Ailin ; Boyd, Richard L. ; Giudice, Antonietta ; Chidgey, Ann P. / A novel Foxn1eGFP/+ mouse model identifies Bmp4-induced maintenance of Foxn1 expression and thymic epithelial progenitor populations. In: European Journal of Immunology. 2017 ; Vol. 47, No. 2. pp. 291-304.
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abstract = "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 Foxn1eGFP/+ 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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author = "Marco Barsanti and Lim, {Joanna M. C.} and Hun, {Michael L.} and Natalie Lister and Kahlia Wong and Hammett, {Maree V.} and Ailin Lepletier and Boyd, {Richard L.} and Antonietta Giudice and Chidgey, {Ann P.}",
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A novel Foxn1eGFP/+ mouse model identifies Bmp4-induced maintenance of Foxn1 expression and thymic epithelial progenitor populations. / Barsanti, Marco; Lim, Joanna M. C.; Hun, Michael L.; Lister, Natalie; Wong, Kahlia; Hammett, Maree V.; Lepletier, Ailin; Boyd, Richard L.; Giudice, Antonietta; Chidgey, Ann P.

In: European Journal of Immunology, Vol. 47, No. 2, 02.2017, p. 291-304.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Barsanti, Marco

AU - Lim, Joanna M. C.

AU - Hun, Michael L.

AU - Lister, Natalie

AU - Wong, Kahlia

AU - Hammett, Maree V.

AU - Lepletier, Ailin

AU - Boyd, Richard L.

AU - Giudice, Antonietta

AU - Chidgey, Ann P.

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N2 - 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 Foxn1eGFP/+ 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.

AB - 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 Foxn1eGFP/+ 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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KW - thymic epithelial cell

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KW - Foxn1dGFP mouse model

KW - thymus development

KW - aging

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