Genomes and Genes
Gene Symbol: Nkx2-1
Description: NK2 homeobox 1
Alias: TTF1, Titf1, homeobox protein Nkx-2.1, TTF-1, thyroid nuclear factor 1, thyroid transcription factor 1 TTF-1 NK-2, thyroid-specific transcription factor 1
- Lee B, Cho G, Norgren R, Junier M, Hill D, Tapia V, et al. TTF-1, a homeodomain gene required for diencephalic morphogenesis, is postnatally expressed in the neuroendocrine brain in a developmentally regulated and cell-specific fashion. Mol Cell Neurosci. 2001;17:107-26 pubmed
- Bruno M, Bohinski R, Huelsman K, Whitsett J, Korfhagen T. Lung cell-specific expression of the murine surfactant protein A (SP-A) gene is mediated by interactions between the SP-A promoter and thyroid transcription factor-1. J Biol Chem. 1995;270:6531-6 pubmed..TTF-1 interacts with complex protein/DNA binding sites located in the 5'-flanking region of the murine SP-A gene enhancing lung epithelial cell-specific expression in vitro. ..
- Lee N, Son Y, Kim J, Ha C, Yun C, Lim H, et al. TTF-1 regulates growth hormone and prolactin transcription in the anterior pituitary gland. Biochem Biophys Res Commun. 2007;362:193-9 pubmed..These data suggest that TTF-1 plays a regulatory role in the transcription of growth hormone and prolactin genes and may regulate transdifferentiation of cells expressing these two hormones. ..
- Kim M, Hur M, Son Y, Park J, Chun S, D Elia A, et al. Regulation of pituitary adenylate cyclase-activating polypeptide gene transcription by TTF-1, a homeodomain-containing transcription factor. J Biol Chem. 2002;277:36863-71 pubmed..Taken together, these data suggest that TTF-1 plays an important regulatory role in the gene transcription for PACAP, which may be important for the generation of a daily rhythm of hypothalamic PACAP gene expression. ..
- Son Y, Hur M, Ryu B, Park S, Damante G, D Elia A, et al. TTF-1, a homeodomain-containing transcription factor, participates in the control of body fluid homeostasis by regulating angiotensinogen gene transcription in the rat subfornical organ. J Biol Chem. 2003;278:27043-52 pubmed..These results demonstrate a novel role for TTF-1 in the regulation of body fluid homeostasis, exerted via the transactivational control of angiotensinogen synthesis in the subfornical organ. ..
- Kim J, Son Y, Yun C, Kim Y, Nam Goong I, Park J, et al. Thyroid transcription factor-1 facilitates cerebrospinal fluid formation by regulating aquaporin-1 synthesis in the brain. J Biol Chem. 2007;282:14923-31 pubmed..These results suggest that TTF-1 is physiologically involved in the transcriptional control of AQP-1, which is required for CSF formation. ..
- Kim J, Nam Goong I, Yun C, Jeong J, Kim E, Park J, et al. TTF-1, a homeodomain-containing transcription factor, regulates feeding behavior in the rat hypothalamus. Biochem Biophys Res Commun. 2006;349:969-75 pubmed..These results suggest a novel role for TTF-1 in the regulation of feeding behavior in the rat hypothalamus. ..
- Ikeda K, Clark J, Shaw White J, Stahlman M, Boutell C, Whitsett J. Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells. J Biol Chem. 1995;270:8108-14 pubmed..The conservation and distribution of TTF-1 in the human respiratory tract support its role in the regulation of lung development and surfactant homeostasis. ..
- Dave V, Childs T, Whitsett J. Nuclear factor of activated T cells regulates transcription of the surfactant protein D gene (Sftpd) via direct interaction with thyroid transcription factor-1 in lung epithelial cells. J Biol Chem. 2004;279:34578-88 pubmed..Components of the calcineurin/NFAT pathway were identified in respiratory epithelial cells of the lung that potentially augment rapid assembly of a multiprotein transcription complex on Sftpd promoter inducing SP-D expression. ..
- Matagne V, Kim J, Ryu B, Hur M, Kim M, Kim K, et al. Thyroid transcription factor 1, a homeodomain containing transcription factor, contributes to regulating periodic oscillations in GnRH gene expression. J Neuroendocrinol. 2012;24:916-29 pubmed publisherThyroid transcription factor 1 (TTF1), a member of the Nkx family of transcription factors required for basal forebrain morphogenesis, functions in the postnatal hypothalamus as a transcriptional regulator of genes encoding ..
- Cao Y, Vo T, Millien G, Tagne J, Kotton D, Mason R, et al. Epigenetic mechanisms modulate thyroid transcription factor 1-mediated transcription of the surfactant protein B gene. J Biol Chem. 2010;285:2152-64 pubmed publisher..Our findings suggest that DNA methylation and chromatin modifications cooperate with Nkx2-1 to regulate Sftpb gene cell specific expression. ..
- Yan C, Sever Z, Whitsett J. Upstream enhancer activity in the human surfactant protein B gene is mediated by thyroid transcription factor 1. J Biol Chem. 1995;270:24852-7 pubmed..In summary, TTF-1 interacts with distinct proximal (-80 to -110) and distal (-439 to -331) cis-acting elements than regulate lung epithelial cell-specific transcription of the human SP-B gene. ..
- Li J, Zhang R, Wang B, Na R, Li Y, Zhao X, et al. [Effects of supplement of thyroxine for hypothyroid pregnant rat on the expression of homeobox gene Nkx2.1 mRNA in the offspring's cerebrum tissue]. Zhonghua Yu Fang Yi Xue Za Zhi. 2010;44:726-30 pubmed..225, 0.336, 0.345, all P values > 0.05). The difference in the expression of homeobox gene Nkx2.1 mRNA is highly related to the level of thyroid hormone. ..
- Takuma N, Sheng H, Furuta Y, Ward J, Sharma K, Hogan B, et al. Formation of Rathke's pouch requires dual induction from the diencephalon. Development. 1998;125:4835-40 pubmedTargeted disruption of the homeobox gene T/ebp (Nkx2.1, Ttf1, Titf1) in mice results in ablation of the pituitary...
- Guazzi S, Price M, De Felice M, Damante G, Mattei M, Di Lauro R. Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity. EMBO J. 1990;9:3631-9 pubmed
- Yuan B, Li C, Kimura S, Engelhardt R, Smith B, Minoo P. Inhibition of distal lung morphogenesis in Nkx2.1(-/-) embryos. Dev Dyn. 2000;217:180-90 pubmed..1 independent, while distal lung morphogenesis appears to be strictly dependent on the wild-type activity of Nkx2.1. ..
- Aurisicchio L, Di Lauro R, Zannini M. Identification of the thyroid transcription factor-1 as a target for rat MST2 kinase. J Biol Chem. 1998;273:1477-82 pubmed..Thus, TTF-1 represents the first identified target of this class of protein kinases. ..
- Endo T, Ohta K, Saito T, Haraguchi K, Nakazato M, Kogai T, et al. Structure of the rat thyroid transcription factor-1 (TTF-1) gene. Biochem Biophys Res Commun. 1994;204:1358-63 pubmed
- Vélez M, Costamagna E, Kimura E, Fozzatti L, Pellizas C, Montesinos M, et al. Bacterial lipopolysaccharide stimulates the thyrotropin-dependent thyroglobulin gene expression at the transcriptional level by involving the transcription factors thyroid transcription factor-1 and paired box domain transcription factor 8. Endocrinology. 2006;147:3260-75 pubmed..The half-lives of TG, Pax8, and TTF-1 are increased in endotoxin-treated cells. Our results reveal the ability of LPS to stimulate the expression of TG, a finding of potential pathophysiological implication. ..
- Konishi T, Kono S, Fujimoto M, Terada T, Matsushita K, Ouchi Y, et al. Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation. J Neurol. 2013;260:207-13 pubmed publisher..The molecular brain imaging and therapeutic response may help elucidate the pathophysiological mechanism of the motor control in the BHC-associated NKX2.1 mutation. ..
- Suzuki M, Katagiri N, Ueda M, Tanaka S. Functional analysis of Nkx2.1 and Pax9 for calcitonin gene transcription. Gen Comp Endocrinol. 2007;152:259-66 pubmed..Pax9 also showed no cooperative effects when it was co-transfected with Nkx2.1. The results suggest that CT gene expression could be directly activated by Nkx2.1, whereas Pax9 is not involved in transcription from the 2kbp CT promoter. ..
- Xu Q, Cobos I, De La Cruz E, Rubenstein J, Anderson S. Origins of cortical interneuron subtypes. J Neurosci. 2004;24:2612-22 pubmed..By establishing spatial differences in the origins of interneuron subtypes, these studies lay the groundwork for elucidating the molecular bases for their distinct differentiation pathways. ..
- Ferrara A, De Michele G, Salvatore E, Di Maio L, Zampella E, Capuano S, et al. A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea. Thyroid. 2008;18:1005-9 pubmed publisher..The aim of this study was to establish the genetic defects that cause that phenotype and study the molecular mechanisms of the pathology...
- Que J, Okubo T, Goldenring J, Nam K, Kurotani R, Morrisey E, et al. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development. 2007;134:2521-31 pubmed..By contrast, Nkx2.1 (Titf1) is expressed ventrally, in the future trachea...
- Maeda Y, Tsuchiya T, Hao H, Tompkins D, Xu Y, Mucenski M, et al. Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. J Clin Invest. 2012;122:4388-400 pubmed publisher..NKX2-1 inhibited both AP-1 activity and tumor colony formation in vitro. These data demonstrate that NKX2-1 functions in a context-dependent manner in lung tumorigenesis and inhibits Kras(G12D)-driven mucinous pulmonary adenocarcinoma. ..
- Koht J, LÃ¸stegaard S, Wedding I, Vidailhet M, Louha M, Tallaksen C. Benign hereditary chorea, not only chorea: a family case presentation. Cerebellum Ataxias. 2016;3:3 pubmed publisher..671Â Tâ€‰>â€‰G (p.Leu224Arg). This family demonstrates well the wide phenotype, including dystonia, myoclonus and ataxia. ..
- Rivas M, Mellstrom B, Naranjo J, Santisteban P. Transcriptional repressor DREAM interacts with thyroid transcription factor-1 and regulates thyroglobulin gene expression. J Biol Chem. 2004;279:33114-22 pubmed..Furthermore, chromatin immunoprecipitation experiments in FRTL-5 cells confirmed that Tg is a bona fide target gene for DREAM transrepression in thyroid follicular cells. ..
- Parlato R, Rosica A, Rodriguez Mallon A, Affuso A, Postiglione M, Arra C, et al. An integrated regulatory network controlling survival and migration in thyroid organogenesis. Dev Biol. 2004;276:464-75 pubmed..The experiments reported here analyze the expression of the transcription factors Titf1, Hhex, Pax8, and Foxe1 in the thyroid primordium of null mutants of each of them...
- Varma S, Cao Y, Tagne J, Lakshminarayanan M, Li J, Friedman T, et al. The transcription factors Grainyhead-like 2 and NK2-homeobox 1 form a regulatory loop that coordinates lung epithelial cell morphogenesis and differentiation. J Biol Chem. 2012;287:37282-95 pubmed publisher..Thus, Grhl2 functions at the nexus of a novel regulatory network, connecting lung epithelial cell identity, migration, and cell-cell interactions. ..
- Dentice M, Luongo C, Elefante A, Ambrosio R, Salzano S, Zannini M, et al. Pendrin is a novel in vivo downstream target gene of the TTF-1/Nkx-2.1 homeodomain transcription factor in differentiated thyroid cells. Mol Cell Biol. 2005;25:10171-82 pubmed..In conclusion, we demonstrate that pendrin and thyroglobulin are downstream targets in vivo of TTF-1, whose action is a prime factor in controlling thyroid differentiation in vivo. ..
- Marin O, Baker J, Puelles L, Rubenstein J. Patterning of the basal telencephalon and hypothalamus is essential for guidance of cortical projections. Development. 2002;129:761-73 pubmed..Furthermore, analysis of the expression of candidate molecules in the basal telencephalon and hypothalamus of Nkx2-1 mutants suggests that Slit2 contributes to this activity. ..
- DeFelice M, Silberschmidt D, DiLauro R, Xu Y, Wert S, Weaver T, et al. TTF-1 phosphorylation is required for peripheral lung morphogenesis, perinatal survival, and tissue-specific gene expression. J Biol Chem. 2003;278:35574-83 pubmed..In contrast to Titf1 null mutant mice, which lack peripheral lung tissues, bronchiolar and peripheral acinar components of the lung ..
- Kolla V, Gonzales L, Gonzales J, Wang P, Angampalli S, Feinstein S, et al. Thyroid transcription factor in differentiating type II cells: regulation, isoforms, and target genes. Am J Respir Cell Mol Biol. 2007;36:213-25 pubmed..In addition, knockdown of TTF-1 inhibited 72 of 274 other genes induced by hormones. We conclude that 42-kD TTF-1 is required for induction of a subset of regulated genes during type II cell differentiation. ..
- Park K, Korfhagen T, Bruno M, Kitzmiller J, Wan H, Wert S, et al. SPDEF regulates goblet cell hyperplasia in the airway epithelium. J Clin Invest. 2007;117:978-88 pubmed..SPDEF was induced following intratracheal allergen exposure and after Th2 cytokine stimulation and was sufficient to cause goblet cell differentiation of Clara cells in vivo. ..
- Butt S, Sousa V, Fuccillo M, Hjerling Leffler J, Miyoshi G, Kimura S, et al. The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes. Neuron. 2008;59:722-32 pubmed publisher..Our strategy reveals a causal link between the embryonic genetic specification by Nkx2-1 in progenitors and the functional attributes of their neuronal progeny in the mature nervous system. ..
- Pakarinen P, Kimura S, El Gehani F, Pelliniemi L, Huhtaniemi I. Pituitary hormones are not required for sexual differentiation of male mice: phenotype of the T/ebp/Nkx2.1 null mutant mice. Endocrinology. 2002;143:4477-82 pubmed..The endogenous testosterone level in the null mutant testes is 5-10% of the control level, which suggests that there is a considerable safety margin in the amount of testosterone that is needed for the male fetal masculinization. ..
- Kusakabe T, Kawaguchi A, Hoshi N, Kawaguchi R, Hoshi S, Kimura S. Thyroid-specific enhancer-binding protein/NKX2.1 is required for the maintenance of ordered architecture and function of the differentiated thyroid. Mol Endocrinol. 2006;20:1796-809 pubmed..Taken together, these results suggest that T/ebp/Nkx2.1 is required for maintenance of the normal architecture and function of differentiated thyroids. ..
- Liu C, Glasser S, Wan H, Whitsett J. GATA-6 and thyroid transcription factor-1 directly interact and regulate surfactant protein-C gene expression. J Biol Chem. 2002;277:4519-25 pubmed..GATA-6 influenced the activity of the sp-C promoter, binding and acting synergistically with TTF-1. ..
- Tell G, Perrone L, Fabbro D, Pellizzari L, Pucillo C, De Felice M, et al. Structural and functional properties of the N transcriptional activation domain of thyroid transcription factor-1: similarities with the acidic activation domains. Biochem J. 1998;329 ( Pt 2):395-403 pubmed..TTF-1 N domain and acidic domains define a family of proteins whose common property is to activate transcription through the use of mechanisms largely conserved during evolutionary development. ..
- Missero C, Pirro M, Di Lauro R. Multiple ras downstream pathways mediate functional repression of the homeobox gene product TTF-1. Mol Cell Biol. 2000;20:2783-93 pubmed..Our data indicate that the Raf/MEK/ERK cascade may act in concert with an as-yet-uncharacterized signaling pathway activated by V12N38 Ras to repress TTF-1 function and ultimately to inhibit thyroid cell differentiation. ..
- Zhou L, Lim L, Costa R, Whitsett J. Thyroid transcription factor-1, hepatocyte nuclear factor-3beta, surfactant protein B, C, and Clara cell secretory protein in developing mouse lung. J Histochem Cytochem. 1996;44:1183-93 pubmed..The early expression of TTF-1 and HNF-3beta, preceding and overlapping that of pro-SP-B, mature SP-B, pro-SP-C, and CCSP, supports a regulatory role for TTF-1 and HNF-3beta in lung-specific gene expression. ..
- Kimura S, Hara Y, Pineau T, Fernandez Salguero P, Fox C, Ward J, et al. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 1996;10:60-9 pubmed..These results establish that the expression of T/EBP, a transcription factor known to control thyroid-specific gene transcription, is also essential for organogenesis of the thyroid, lung, ventral forebrain, and pituitary. ..
- Chen H, Zhang J, Huang H, Wang Z, Cheng R, Cai W. Leptin promotes fetal lung maturity and upregulates SP-A expression in pulmonary alveoli type-II epithelial cells involving TTF-1 activation. PLoS ONE. 2013;8:e69297 pubmed publisher..These results suggest that leptin may have great therapeutic potential for the treatment of FGR, and leptin-mediated SP-A induction and lung maturity of the fetus are TTF-1 dependent. ..
- McMichael G, Haan E, Gardner A, Yap T, Thompson S, Ouvrier R, et al. NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy. Eur J Med Genet. 2013;56:506-9 pubmed publisher..Screening of 60 unrelated individuals with a diagnosis of dyskinetic or ataxic CP did not identify NKX2-1 mutations. BHC can be confused with ataxic and dyskinetic CP. Occasionally these children have a mutation in NKX2-1. ..
- Abramowicz M, Vassart G, Christophe D. Functional study of the human thyroid peroxidase gene promoter. Eur J Biochem. 1992;203:467-73 pubmed
- Nettore I, Mirra P, Ferrara A, Sibilio A, Pagliara V, Kay C, et al. Identification and functional characterization of a novel mutation in the NKX2-1 gene: comparison with the data in the literature. Thyroid. 2013;23:675-82 pubmed publisher..NKX2-1 mutations have been described in several patients with primary congenital hypothyroidism, respiratory distress, and benign hereditary chorea, which are classical manifestations of the brain-thyroid-lung syndrome (BTLS)...
- Amendola E, Sanges R, Galvan A, Dathan N, Manenti G, Ferrandino G, et al. A locus on mouse chromosome 2 is involved in susceptibility to congenital hypothyroidism and contains an essential gene expressed in thyroid. Endocrinology. 2010;151:1948-58 pubmed publisher..development of congenital hypothyroidism in mice heterozygous for null mutations in genes encoding Nkx2-1/Titf1 and Pax8...
- Ngan E, Lang B, Liu T, Shum C, So M, Lau D, et al. A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma. J Natl Cancer Inst. 2009;101:162-75 pubmed publisher..This is the first germline mutation identified in MNG/PTC patients. It could contribute to predisposition for MNG and/or PTC and to the pathogenesis of PTC. ..
- Yin Z, Gonzales L, Kolla V, Rath N, Zhang Y, Lu M, et al. Hop functions downstream of Nkx2.1 and GATA6 to mediate HDAC-dependent negative regulation of pulmonary gene expression. Am J Physiol Lung Cell Mol Physiol. 2006;291:L191-9 pubmed..Thus Hop represents a novel regulator of pulmonary maturation that is induced by glucocorticoids to mediate functionally important HDAC-dependent negative feedback regulation. ..
- Di Palma T, Nitsch R, Mascia A, Nitsch L, Di Lauro R, Zannini M. The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription. J Biol Chem. 2003;278:3395-402 pubmed
- Zhang Y, Rath N, Hannenhalli S, Wang Z, Cappola T, Kimura S, et al. GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo. Development. 2007;134:189-98 pubmed..However, the relevance of this synergy has not been demonstrated in vivo. We show that Gata6-Titf1 (Gata6-Nkx2...
- Weidenfeld J, Shu W, Zhang L, Millar S, Morrisey E. The WNT7b promoter is regulated by TTF-1, GATA6, and Foxa2 in lung epithelium. J Biol Chem. 2002;277:21061-70 pubmed..Together, these results suggest that WNT7b gene expression in the lung epithelium is regulated in a combinatorial fashion by TTF-1, GATA6, and Foxa2. ..
- Zighelboim I, Goodfellow P, Schmidt A, Walls K, Mallon M, Mutch D, et al. Differential methylation hybridization array of endometrial cancers reveals two novel cancer-specific methylation markers. Clin Cancer Res. 2007;13:2882-9 pubmed..DMH and COBRA identified two CpG islands methylated in tumors but not in normal DNAs: SESN3 (PY2B4) and TITF1 (SC77F6/154). Bisulfite sequencing showed dense methylation of the CpG islands and confirmed the COBRA assays...
- Xu B, O DONNELL M, O Donnell J, Yu J, Zhang Y, Sartor M, et al. Adipogenic Differentiation of Thyroid Cancer Cells Through the Pax8-PPAR? Fusion Protein Is Regulated by Thyroid Transcription Factor 1 (TTF-1). J Biol Chem. 2016;291:19274-86 pubmed publisher..Our data indicate that TTF-1 interacts with PPFP to inhibit the pro-adipogenic response to pioglitazone, and that the ability of pioglitazone to decrease TTF-1 expression contributes to its pro-adipogenic action. ..
- Zhu N, Li C, Xiao J, Minoo P. NKX2.1 regulates transcription of the gene for human bone morphogenetic protein-4 in lung epithelial cells. Gene. 2004;327:25-36 pubmed..1. These findings bear functional implications regarding the regulation of a key signaling molecule by a homeodomain transcriptional regulator of lung epithelial morphogenesis. ..
- Serls A, Doherty S, Parvatiyar P, Wells J, Deutsch G. Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung. Development. 2005;132:35-47 pubmed..Together, the findings suggest that a concentration threshold of FGFs emanating from the cardiac mesoderm are involved in patterning the foregut endoderm. ..
- Uemae Y, Sakamoto J, Hidaka Y, Hiratsuka A, Susa T, Kato Y, et al. Gene expression, function, and diversity of Nkx2-4 in the rainbow trout, Oncorhynchus mykiss. Gen Comp Endocrinol. 2014;206:193-202 pubmed publisher..The results suggest that in the rainbow trout, Nkx2-4a and Nkx2-4b might play a major role in TG gene transcription whereas Nkx2-4c might have some functions in the ovary as well as the thyroid. ..
- Acebron A, Aza Blanc P, Rossi D, Lamas L, Santisteban P. Congenital human thyroglobulin defect due to low expression of the thyroid-specific transcription factor TTF-1. J Clin Invest. 1995;96:781-5 pubmed..Moreover, these data suggest that TTF-1 and Pax-8 would be differentially regulating thyroglobulin and thyroperoxidase gene transcription. ..
- Stahlman M, Gray M, Whitsett J. Expression of thyroid transcription factor-1(TTF-1) in fetal and neonatal human lung. J Histochem Cytochem. 1996;44:673-8 pubmed
- Reiser H, Schneeberger E. Expression and function of B7-1 and B7-2 in hapten-induced contact sensitivity. Eur J Immunol. 1996;26:880-5 pubmed..Experiments in which mice are injected differentially with anti-B7-2 mAb, either before the afferent or before the efferent phase of the contact sensitivity response, suggest that B7-2 is important for successful antigen priming. ..