Disease relevance of Titf1

• To determine whether the hypothyroidism is of central or primary origin, we examined the bioactivity of TSH, thyroidal response to exogenous TSH and the expression of genes regulated by TTF1 [1].
• Increased expression of TTF-1 altered alveolarization and caused chronic pulmonary inflammation, demonstrating that precise regulation of TTF-1 is critical for homeostasis in the postnatal lung [2].
• In mice with the highest transgene expression, TTF-1 caused severe inflammation, pulmonary fibrosis, respiratory failure, and death, associated with eosinophil infiltration and increased expression of eotaxin and IL-6 [2].
• In contrast, higher expression levels of TTF-1 disrupted alveolar septation, causing emphysema [2].
• Modest overexpression of TTF-1 caused type II cell hyperplasia and increased the cellular content of SP-B [2].

Psychiatry related information on Titf1

• Transcriptional factors including Nkx2.1, HNF family forkhead homologues, GATA family zinc finger factors, pou and hox, helix-loop-helix (HLH) factors, Id factors, glucocorticoid and retinoic acid receptors mediate and integrate the developmental genetic instruction of lung morphogenesis and cell lineage determination [3].

High impact information on Titf1

• Mice lacking the transcription factor Ttf1 lack both cell types and thus are unable to develop a thyroid gland [4].
• The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary [5].
• The thyroid-specific enhancer-binding protein (T/ebp) gene was disrupted by homologous recombination in embryonic stem cells to generate mice lacking T/EBP expression [5].
• Two-step regulation of left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance by Nkx2 [6].
• These results suggest that the left-sided expression of Pitx2 is directly initiated by Nodal signaling and is subsequently maintained by Nkx2 [6].

Chemical compound and disease context of Titf1

• BACKGROUND/PURPOSE: The well-established Adriamycin rat model of oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) complements recently described mouse genetic models in which loss of function mutations in foregut patterning genes, such as Nkx2.1 (Ttf 1), lead to OA/TOF [7].

Biological context of Titf1

• Targeted disruption of the homeobox gene T/ebp (Nkx2.1, Ttf1, Titf1) in mice results in ablation of the pituitary [8].
• Thus, in contrast to the null Titf1 mutation, the Titf1PM/PM mutant substantially restored lung morphogenesis [9].
• We report here that in mouse models, the combination of partial deficiencies in the Titf1 and Pax8 genes results in an overt TD phenotype that is absent in either of the singly deficient, heterozygous mice [10].
• Failure of the mutant TTF1 to interfere with binding and transactivation functions of the wild-type TTF1 suggested that the syndrome was caused by haploinsufficiency [11].
• The mutant TTF1 did not bind to its canonical cis-element or transactivate a reporter gene driven by the thyroglobulin promoter, a natural target of TTF1 [11].

Anatomical context of Titf1

• In particular, no TTF1 gene defects were found in 76 individuals with thyroid dysgenesis even though a deletion of this gene in the mouse results in thyroid and lung agenesis and defective diencephalon [11].
• Molecular analyses indicated that expression of Shh, Nkx2.1 and BF-1 was increased and their expression domains expanded dorsally in the ventral telencephalon in embryos of diabetic mice at embryonic day 11 [12].
• Increased expression of thyroid transcription factor-1 (TTF-1) in respiratory epithelial cells inhibits alveolarization and causes pulmonary inflammation [2].
• Thyroid transcription factor-1 (TTF-1), a member of the Nkx2 family of homeodomain-containing transcription factors, is expressed in the epithelium of the lung [2].
• To test the hypothesis that NFI isoforms interact with TTF-1 to differentially regulate SP-C transcription, we performed transient transfection assays in JEG-3 cells, a choriocarcinoma cell line with negligible endogenous NFI or TTF-1 activity [13].

Associations of Titf1 with chemical compounds

• One allele of his TTF1 gene had a guanidine inserted into codon 86 producing a nonsense protein of 407, rather than 371, amino acids [11].
• Induction of NFIen in a subset of type II cells inhibited SP-C gene expression without affecting expression of TTF-1 in doxycycline-treated double-transgenic mice [13].
• The mRNA for one gene (TTF-1), unchanged during hyperoxia, was upregulated late in recovery phase [14].
• To assess the role of TTF-1 and its phosphorylation during lung morphogenesis, mice bearing a mutant allele, in which seven serine phosphorylation sites were mutated, Titf1PM/PM, were generated by homologous recombination [9].
• Temporal-spatial expression and transcriptional regulation of alpha7 nicotinic acetylcholine receptor by thyroid transcription factor-1 and early growth response factor-1 during murine lung development [15].

Physical interactions of Titf1

• Mammalian two-hybrid assays and pull-down experiments demonstrated that the TAZ directly interacted with TTF-1 [16].
• Gel- retardation assays and mutagenesis experiments revealed the presence of functionally relevant TTF-1 binding sites in the Hex promoter region [17].
• A proximal AP-1 binding site (-18 to -10 bp) was identified that overlaps a thyroid transcription factor-1 binding site [18].

Regulatory relationships of Titf1

• TTF-1 regulates expression of MK in the lung [19].
• By contrast, as indicated by both loss- and gain-of-function analysis, Gsh2 expression in the medial ganglionic eminence after E10.5 may negatively regulate Nkx2.1 dependent specification of oligodendrocytes [20].
• However, the remaining tissues reconstituted Gsc and Shh activity and expressed the ventral forebrain marker Nkx2 [21].
• A model is also supported whereby alpha(7) is induced by the essential pulmonary transcription factor TTF-1 and suppressed by Egr-1 during pulmonary development [15].
• 5. We further demonstrate that the procollagen lysyl hydroxylase (PLOD1) promoter is regulated by Nkx2 [22].

Other interactions of Titf1

• In this study, we demonstrate synergistic transactivation by C/EBPalpha and Nkx2.1 in the regulation of the CCSP gene [23].
• Furthermore, MK expression was not detected in lungs of TTF-1 null mice [19].
• Early cardiac development might therefore be regulated by other genes, which may act either independently or in concert with Csx/Nkx2 [24].
• Moreover, we show that Pax8 and TTF-1 cooperate in the activation of the thyroglobulin promoter and that additional thyroid-specific mechanism(s) are involved in such a cooperation [25].
• Notably, in the prospective amygdala region where Shh expression persists in the Nkx2.1 mutant, the presence of plp/dm20 is unperturbed [26].

Analytical, diagnostic and therapeutic context of Titf1

• Thyroid mRNAs were measured by real-time PCR (Ttf1+/+ littermates = 100%) [1].
• Electrophoretic mobility shift assays showed that TTF-1, GATA6, and Foxa2 can bind to a specific subset of their consensus DNA binding sites within the WNT7b promoter [27].
• Using immunohistochemistry, northern blot or western blot, tumours were found to express the transcription factor TTF-1, as well as specific markers of the peripheral airway Clara cells (CC10) and alveolar type II cells (surfactant proteins A, B, C, and D) [28].
• Immunocytochemistry showed that with T(3) treatment, Nkx2.1 and surfactant protein SP-C proteins became progressively localized to cuboidal epithelial cells and mesenchymal expression of Hoxb5 was reduced, a pattern resembling late fetal lung development [29].
• By RT-PCR, we found that lung SP cells express hepatocyte nuclear factor-3beta, but not thyroid transcription factor-1 [30].

References