Foxe1 Deletion in the Adult Mouse Is Associated With Increased Thyroidal Mast Cells and Hypothyroidism

Grace Lim; Alexander Widiapradja; Scott P Levick; Kelly J McKelvey; Xiao-Hui Liao; Samuel Refetoff; Martyn Bullock; Roderick J Clifton-Bligh

doi:10.1210/endocr/bqac158

Foxe1 Deletion in the Adult Mouse Is Associated With Increased Thyroidal Mast Cells and Hypothyroidism

Endocrinology. 2022 Oct 23;163(12):bqac158. doi: 10.1210/endocr/bqac158.

Authors

Grace Lim¹, Alexander Widiapradja², Scott P Levick², Kelly J McKelvey³, Xiao-Hui Liao⁴, Samuel Refetoff⁵, Martyn Bullock¹, Roderick J Clifton-Bligh^{1

6}

Affiliations

¹ Cancer Genetics Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW 2065, Australia.
² Cardiac Biology and Heart Failure Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW 2065, Australia.
³ Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW 2065, Australia.
⁴ Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
⁵ Department of Medicine, Pediatrics and Committee on Genetics, The University of Chicago, Chicago, Illinois 60637, USA.
⁶ Department of Endocrinology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.

Abstract

Context: Foxe1 is a key thyroid developmental transcription factor. Germline deletion results in athyreosis and congenital hypothyroidism. Some data suggest an ongoing role for maintaining thyroid differentiation.

Objective: We created a mouse model to directly examine the role of Foxe1 in the adult thyroid.

Methods: A model of tamoxifen-inducible Cre-mediated ubiquitous deletion of Foxe1 was generated in mice of C57BL/6J background (Foxe1flox/flox/Cre-TAM). Tamoxifen or vehicle was administered to Foxe1flox/flox/Cre mice aged 6-8 weeks. Blood was collected at 4, 12, and 20 weeks, and tissues after 12 or 20 weeks for molecular and histological analyses. Plasma total thyroxine (T4), triiodothyronine, and thyrotropin (TSH) were measured. Transcriptomics was performed using microarray or RNA-seq and validated by reverse transcription quantitative polymerase chain reaction.

Results: Foxe1 was decreased by approximately 80% in Foxe1flox/flox/Cre-TAM mice and confirmed by immunohistochemistry. Foxe1 deletion was associated with abnormal follicular architecture and smaller follicle size at 12 and 20 weeks. Plasma TSH was elevated in Foxe1flox/flox/Cre-TAM mice as early as 4 weeks and T4 was lower in pooled samples from 12 and 20 weeks. Foxe1 deletion was also associated with an increase in thyroidal mast cells. Transcriptomic analyses found decreased Tpo and Tg and upregulated mast cell markers Mcpt4 and Ctsg in Foxe1flox/flox/Cre-TAM mice.

Conclusion: Foxe1 deletion in adult mice was associated with disruption in thyroid follicular architecture accompanied by biochemical hypothyroidism, confirming its role in maintenance of thyroid differentiation. An unanticipated finding was an increase in thyroidal mast cells. These data suggest a possible explanation for previous human genetic studies associating alleles in/near FOXE1 with hypothyroidism and/or autoimmune thyroiditis.

Keywords: FOXE1; autoimmune thyroiditis; hypothyroidism; mast cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cathepsin G
Congenital Hypothyroidism*
Forkhead Transcription Factors / genetics
Mast Cells*
Mice
Mice, Inbred C57BL
Tamoxifen
Thyrotropin
Thyroxine

Substances

Cathepsin G
Ctsg protein, mouse
Forkhead Transcription Factors
FOXE1 protein, human
Foxe1 protein, mouse
Tamoxifen
Thyrotropin
Thyroxine

Grants and funding

R01 DK015070/DK/NIDDK NIH HHS/United States