FOXE1

FOXE1 gene encodes a protein also known as Thyroid Transcription Factor 2 (TTF-2) [R].

The FOXE1 protein regulates the transcription of thyroglobulin (Tg) and thyroid peroxidase (TPO). [R]

The FOXE1 gene variations associated with risk of development of several cancer types.

FOXE1 protein implicated in:

• differentiation and development of thyroid cells [R], [R], [R], [R], [R]

• development of several cancer types [R], [R], [R], [R], [R], [R], [R], [R], [R], [R]

• Bamforth -Lazarus syndrome [R], [R], [R]

• Non-syndromic cleft lip with or without cleft palate (NS CL/P) disease [R], [R]

• Premature ovarian failure (POF) disease [R]

The exact role for FOXE1 in thyroid and cancer developments and the underlying mechanisms remain poorly understood. [R]

Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription. Involved in proper palate formation, most probably through the expression of MSX1 and TGFB3 genes which are direct targets of this transcription factor. Also implicated in thyroid gland morphogenesis. May indirectly play a role in cell growth and migration through the regulation of WNT5A expression.

The FOXE1 gene encodes a DNA-binding protein also known as thyroid transcription factor 2 (TTF-2), a member of the forkhead/winged-helix family of evolutionarily conserved transcription factors. [R]

The FOXE1 protein:

• has also other names: FKHL15, FOXE2, HFKH4, HFKL5, TITF2, TTF-2, TTF2. [R]  

• regulates the transcription of thyroglobulin (Tg) and thyroid peroxidase (TPO). [R]

• plays a crucial role in thyroid development. [R]

• plays an important role in secondary palate closure and hair follicle morphogenesis. [R]

The mutations in FOXE1gene associated:

• with non-syndromic cleft lip with or without cleft palate (NS CL/P).[R], [R], [R], [R]

• with Bamforth-Lazarus syndrome. [R]

• implicated in Premature Ovarian Failure (POF) disease [R]

The role of FOXE1 in Thyroid Development.[R]

FOXE1 is called as a specific core protein of thyroid gland [R],

FOXE1 is expressed at the embryonic Carnegie stage (CS) 15 in the thyroid primordium and persists in the thyroid gland throughout development. At the same embryonic stage, FOXE1 is also detectable in the thymus and in the oropharyngeal epithelium. At 11 weeks of development, it is present in the tracheal and esophageal epithelium [R].

FOXE1 is a key player in thyroid organogenesis and thyrocyte precursor migration and differentiation [R].

In adulthood, FOXE1 is detectible in thyroid and hair follicles, and in prepubertal testis [R].

Although the available data strongly support a role for FOXE1 in thyroid development, the underlying mechanisms remain poorly understood. [R]

Researchers suggested:

1) FOXE1 may be a component of one or more networks. During thyroid organogenesis, FOXE1 expression by the future thyroid cells at the very early anlage stage (specification phase) occurs concomitantly with the expression of other transcription factors including TITF1 (formerly called TTF-1/NKX2.1), PAX8 [R], and HHEX (formerly called HEX) [R].

The hypothesis of a network has received support from a study in mice indicating precise spatial regulation of Foxe1 expression, which depends on Pax8 in the thyroid bud and on Shh in the neighboring pharyngeal cells [R].

The regulatory interactions between Foxe1 and other transcription factors may act as a fail-safe mechanism that leads to the disappearance of thyroid cell precursors if any of the genes malfunction early during development since each gene initiates a chain of events leading to the complete removal of thyroid cells [R].

2) Alternatively, FOXE1 may affect thyroid development via some of the target genes, which would explain the variability of the FOXE1-altered phenotype. Several genes upregulated by FOXE1 were identified recently [R] and some of them might play a role in thyroid development, while others might exert global effects on the development of multiple organs. However, although the variable expression of the FOXE1-altered phenotype supports a role for additional genetic or stochastic events during organogenesis, the individual genetic background or sex-related factors may also be involved.

The genetic alterations of FOXE1 lead to abnormal thyroid development. Mutations within the forkhead domain are responsible for syndromic CH with TD (ranging from severe hypoplasia to athyreosis), cleft palate, and spiky hair. The length of the FOXE1 polyalanine tract may affect the susceptibility to TD, most likely depending on additional genetic or stochastic events during organogenesis, as well as on individual genetic factors or sex-related factors. [R]

Role of FOXE1 gene in development of several cancer types:

• thyroid carcinomas [R], [R], [R]

• basal and squamous cell carcinomas of the skin [R], [R]

• breast cancer [R], [R]

• pancreatic cancer [R], [R].

• papillary carcinomas [R],

• follicular adenomas and carcinomas poorly differentiated thyroid carcinomas [R].

• higher Papillary Thyroid Cancer susceptibility. [R]

• FOXE1 exhibited cytoplasmic overexpression in tumor tissue compared to the normal counterpart. Both cancer and normal thyroid cells demonstrated the highest FOXE1 scores in the areas closest to the tumor border compared with more distant areas [R]

     From NCBI Gene: Thyroid cancer, nonmedullary, 4Bamforth syndromeFrom UniProt: Thyroid cancer, non-medullary, 4 (NMTC4): A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. [MIM:616534] Bamforth-Lazarus syndrome (BLS): A disease characterized by thyroid agenesis, cleft palate and choanal atresia. [MIM:241850]

     From NCBI Gene: This intronless gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. This gene functions as a thyroid transcription factor which likely plays a crucial role in thyroid morphogenesis. Mutations in this gene are associated with congenital hypothyroidism and cleft palate with thyroid dysgenesis. The map localization of this gene suggests it may also be a candidate gene for squamous cell epithelioma and hereditary sensory neuropathy type I. [provided by RefSeq, Jul 2008] From UniProt: Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription. Involved in proper palate formation, most probably through the expression of MSX1 and TGFB3 genes which are direct targets of this transcription factor. Also implicated in thyroid gland morphogenesis. May indirectly play a role in cell growth and migration through the regulation of WNT5A expression.