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FOXN1 forms higher-order nuclear condensates displaced by mutations causing immunodeficiency.

Ioanna A Rota1, Adam E Handel1,2, Stefano Maio1

  • 1Department of Paediatrics and the MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Science Advances
|December 3, 2021
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Summary
This summary is machine-generated.

The transcription factor FOXN1 regulates thymus development. A C-terminal mutation causes a dominant-negative effect, leading to primary immunodeficiency by disrupting nuclear condensates and TEC differentiation.

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Area of Science:

  • Molecular Biology
  • Immunology
  • Developmental Biology

Background:

  • The transcription factor FOXN1 is crucial for thymic epithelial cell (TEC) development and function.
  • FOXN1's role in organogenesis and its precise regulatory mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the role of FOXN1 expression regulation during organogenesis.
  • To elucidate the mechanism of FOXN1's transcriptional activity and its involvement in nuclear condensates.
  • To identify the cause of a primary immunodeficiency disease linked to a FOXN1 mutation.

Main Methods:

  • Analysis of FOXN1 expression during organogenesis.
  • Investigation of FOXN1's participation in multimolecular nuclear condensates.
  • Characterization of a patient-derived mutant FOXN1 with altered C-terminal sequence.
  • Assessment of the mutant FOXN1's dominant-negative effect on TEC differentiation in vitro and in vivo mouse models.

Main Results:

  • FOXN1 expression is differentially regulated during organogenesis and forms essential nuclear condensates for transcriptional activity.
  • The C-terminal sequence of FOXN1 dictates its diffusion within condensates and binding to gene regulatory regions.
  • A patient with a C-terminal FOXN1 mutation exhibits a transcriptionally inactive mutant that acts in a dominant-negative manner.
  • The mutant FOXN1 displaces wild-type FOXN1, causing athymia and severe lymphopenia in heterozygotes, and selectively impairs mouse TEC differentiation in a gene dose-dependent manner.

Conclusions:

  • The study identifies a FOXN1 gain-of-function mutant as the cause of a primary immunodeficiency disease.
  • The mechanism involves the mutant FOXN1 disrupting wild-type FOXN1 function within nuclear condensates, impairing TEC development.
  • This research highlights the critical role of FOXN1 dynamics in nuclear condensates for normal thymus organogenesis and immune function.