Foxe1, also known as TTF-2, is a thyroid-specific transcription factor essential for thyroid gland development and maintaining the differentiated state. It is involved in various biological processes and has been associated with multiple pathways. Mutations in Foxe1 are linked to congenital hypothyroidism due to thyroid dysgenesis, often accompanied by cleft palate and other features in humans [2]. Genetic models, such as mouse models, have been crucial in understanding its function.

In psoriasis, Foxe1 expression is increased in lesional skin. Knockdown and over-expression experiments in keratinocytes (KCs) showed that Foxe1 promotes KC proliferation by facilitating G1/S transition and activating the extracellular signal-regulated kinase 1/2 signaling pathway. It also affects the production of cytokines like IL-1β, IL-6, and TNF-α by KCs. RNA-sequencing identified WNT5A as a potential downstream effector, and knockdown of WNT5A mitigated the effects of Foxe1 [1]. In thyroid cancer, in vivo studies using mice with reduced Foxe1 gene dosage (FOXE1+/-) crossed with a BRAFV600E-inducible cancer model showed that lower Foxe1 levels led to cancers with less malignant morphological features, reduced proliferation, increased apoptosis, but also severe undifferentiation, indicating its role in thyroid differentiation during neoplastic transformation [3]. Additionally, in a tamoxifen-inducible Cre-mediated ubiquitous deletion of Foxe1 mouse model (Foxe1flox/flox/Cre-TAM), Foxe1 deletion in adult mice was associated with abnormal follicular architecture, smaller follicle size, elevated TSH, lower T4, and an increase in thyroidal mast cells, confirming its role in maintaining thyroid differentiation [4].

In conclusion, Foxe1 is essential for thyroid gland development and differentiation. Model-based research, especially using KO or CKO mouse models, has revealed its significance in diseases such as psoriasis and thyroid-related disorders. These studies help in understanding the biological functions of Foxe1 and provide potential targets for treatment in these disease areas.

References:

1. Liu, Meng, Zhang, Guanfei, Wang, Ziyang, Zheng, Yan, Shao, Yongping. 2023. FOXE1 Contributes to the Development of Psoriasis by Regulating WNT5A. In The Journal of investigative dermatology, 143, 2366-2377.e7. doi:10.1016/j.jid.2023.04.035. https://pubmed.ncbi.nlm.nih.gov/37394057/

2. Castanet, Mireille, Polak, Michel. 2010. Spectrum of Human Foxe1/TTF2 Mutations. In Hormone research in paediatrics, 73, 423-9. doi:10.1159/000281438. https://pubmed.ncbi.nlm.nih.gov/20453517/

3. Credendino, Sara C, Moccia, Carmen, Amendola, Elena, De Felice, Mario, De Vita, Gabriella. 2020. FOXE1 Gene Dosage Affects Thyroid Cancer Histology and Differentiation In Vivo. In International journal of molecular sciences, 22, . doi:10.3390/ijms22010025. https://pubmed.ncbi.nlm.nih.gov/33375029/

4. Lim, Grace, Widiapradja, Alexander, Levick, Scott P, Bullock, Martyn, Clifton-Bligh, Roderick J. . Foxe1 Deletion in the Adult Mouse Is Associated With Increased Thyroidal Mast Cells and Hypothyroidism. In Endocrinology, 163, . doi:10.1210/endocr/bqac158. https://pubmed.ncbi.nlm.nih.gov/36156081/