Thyroid transcription factor-1 (TTF-1) is aprotein that regulatestranscription ofgenes specific for thethyroid,lung, anddiencephalon. It is also known as thyroid specific enhancer binding protein. It is used inanatomic pathology as a marker to determine if atumor arises from the lung or thyroid. NKX2.1 can be induced byactivin A viaSMAD2 signaling in a human embryonic stem cell differentiation model.[7]
NKX2.1 is key to the fetal development of lung structures. The dorsal-ventral pattern of NKX2.1 expression forms the ventral boundary in the anterior foregut. NKX2.1 is expressed only in select cells in the ventral wall of theanterior foregut, and is not expressed in the dorsal wall, where theesophagus will emerge from.
NKX2.1knockout in mice results in the development of a shortenedtrachea which is fused to the esophagus, with thebronchi directly connecting this shared tube to the lungs. This resembles acomplete tracheoesophageal fistula, which is a rarecongenital condition in humans. Distal lung structures do not develop in these knockout mice. Branching of the lungs in these mice did not occur past the main-stem bronchi, resulting in lungs that were smaller in size by about 50% compared to thewild-type mice. Theepithelial lining of these distal structures did not show evidence of differentiation into specialized cells. This lining is composed of columnar epithelial cells and scattered ciliated epithelial cells.[8] The proximal epithelium of the lungs showed normal differentiation, indicating that proximal differentiation is independent of NKX2.1. NKX2.1 is initially expressed in the entire epithelium, but is suppressed in a proximal-distal pattern as the lung continues to develop.[9]
TTF-1 needs to have nuclear staining on immunohistochemistry to count as positive. Cytoplasmic staining is disregarded for diagnostic purposes.[10]Micrograph of a metastatic lung adenocarcinoma (found in the brain) that exhibits nuclear staining (brown) forTTF-1.
It has been observed that a loss of Nkx2-1 allows for deregulation of transcription factorsFOXA1/2 (by relaxinghistone deacetylation andmethylation-mediated repression of Foxa1/2 by Nkx2-1) causing reactivation of an embryonic gastric differentiation program in pulmonary cells. This results inmucinous lung adenocarcinoma, a source of poor clinical outcomes for patients.[15]
However others have found that TTF-1 staining is often positive in pulmonary adenocarcinomas, large cell carcinomas, small-cell lung carcinomas, neuroendocrine tumors other than small-cell lung carcinomas and extrapulmonary small-cell carcinomas.[16]
^Image by Mikael Häggström, MD. Source for significance:Bejarano PA, Mousavi F (2003). "Incidence and significance of cytoplasmic thyroid transcription factor-1 immunoreactivity".Arch Pathol Lab Med.127 (2):193–5.doi:10.5858/2003-127-193-IASOCT.PMID12562233.
Oguchi H, Pan YT, Kimura S (April 1995). "The complete nucleotide sequence of the mouse thyroid-specific enhancer-binding protein (T/EBP) gene: extensive identity of the deduced amino acid sequence with the human protein".Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression.1261 (2):304–6.doi:10.1016/0167-4781(95)00033-D.PMID7711079.
Saiardi A, Tassi V, De Filippis V, Civitareale D (April 1995). "Cloning and sequence analysis of human thyroid transcription factor 1".Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression.1261 (2):307–10.doi:10.1016/0167-4781(95)00034-E.PMID7711080.
Hamdan H, Liu H, Li C, Jones C, Lee M, deLemos R, Minoo P (March 1998). "Structure of the human Nkx2.1 gene".Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression.1396 (3):336–48.doi:10.1016/S0167-4781(97)00210-8.PMID9545595.
Naltner A, Wert S, Whitsett JA, Yan C (December 2000). "Temporal/spatial expression of nuclear receptor coactivators in the mouse lung".American Journal of Physiology. Lung Cellular and Molecular Physiology.279 (6): L1066-74.doi:10.1152/ajplung.2000.279.6.l1066.PMID11076796.S2CID27872061.
