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Shao-Chiang Lai, Cody A Phelps, Aleena M Short, Sucharita M Dutta, David Mu
We have discovered an unexpected connection between a critical lung development and cancer gene termed thyroid transcription factor 1 (TTF-1 also known as NKX2-1) and cholesterol metabolism. Our published work implicates that TTF-1 positively regulates miR-33a which is known to repress ATP-binding cassette transporter 1 (ABCA1) and thus its cholesterol efflux activity. We set out to demonstrate that a higher TTF-1 expression would presumably inhibit cholesterol efflux and consequently raise intracellular cholesterol level...
March 19, 2018: Oncogene
Minjing Zou, Ali S Alzahrani, Ali Al-Odaib, Mohammad A Alqahtani, Omer Babiker, Roua A Al-Rijjal, Huda A BinEssa, Walaa E Kattan, Anwar F Al-Enezi, Ali Al Qarni, Manar S A Al-Faham, Essa Y Baitei, Afaf Alsagheir, Brian F Meyer, Yufei Shi
Context: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000-4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied. Objective: To identify mutation spectrum of CH-causing genes. Methods: Fifty-five patients from 47 families were studied by next-generation-exome sequencing...
March 12, 2018: Journal of Clinical Endocrinology and Metabolism
Stephanie J Attarian, Sandra L Leibel, Ping Yang, Danielle N Alfano, Brian P Hackett, F Sessions Cole, Aaron Hamvas
BACKGROUND: Mutations in the NKX2-1 gene are associated with lung disease in infants and children. We hypothesize that disruption of normal surfactant gene expression with these mutations contributes to the respiratory phenotypes observed. METHODS: To assess transactivational activity, co-transfection of luciferase reporter vectors containing surfactant protein B or C (SFTPB or SFTPC) promoters with NKX2-1 plasmids was performed and luciferase activity measured...
March 14, 2018: Pediatric Research
Wei Zhang, Luc Girard, Yu-An Zhang, Tomohiro Haruki, Mahboubeh Papari-Zareei, Victor Stastny, Hans K Ghayee, Karel Pacak, Trudy G Oliver, John D Minna, Adi F Gazdar
Background: Small cell lung cancer (SCLC) is a deadly, high grade neuroendocrine (NE) tumor without recognized morphologic heterogeneity. However, over 30 years ago we described a SCLC subtype with "variant" morphology which did not express some NE markers and exhibited more aggressive growth. Methods: To quantitate NE properties of SCLCs, we developed a 50-gene expression-based NE score that could be applied to human SCLC tumors and cell lines, and genetically engineered mouse (GEM) models...
February 2018: Translational Lung Cancer Research
Nadia Nathan, Keren Borensztajn, Annick Clement
PURPOSE OF REVIEW: Interstitial lung disease (ILD) in children (chILD) is an umbrella term for a heterogeneous group of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. The pathogenesis of the various chILD is complex and implicates genetic contributors. The purpose of this review is to provide updated information on the molecular defects associated with the development of chILD. RECENT FINDINGS: Currently, the main mutations are identified in the surfactant genes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3, and NKX2-1...
March 6, 2018: Current Opinion in Pulmonary Medicine
Ritu Mishra, Houda Benlhabib, Wei Guo, Connie B Lerma Cervantes, Carole R Mendelson
The major surfactant protein, SP-A (product of SFTPA gene), serves as a marker of type II pneumocyte differentiation and surfactant synthesis. SFTPA expression in cultured human fetal lung (HFL) epithelial cells is upregulated by hormones that increase cAMP and activate TTF-1/NKX2.1 and NF-κB. To further define mechanisms for type II cell differentiation and induction of SP-A, we investigated roles of miRNAs. Using microarray to identify differentially expressed miRNAs in HFL epithelial cells during type II cell differentiation in culture, we observed that members of the miR-199a/-214 cluster were significantly downregulated during differentiation...
March 5, 2018: Molecular and Cellular Biology
Beatriz Villafuerte, Daniel Natera-de Benito, Aidy González, María A Mori, María Palomares, Julián Nevado, Sixto García-Miñaur, Pablo Lapunzina, Luis I González-Granado, Luis M Allende, José C Moreno
Genetic defects of NKX2-1 are classically associated with hypothyroidism, benign chorea and neonatal respiratory distress. The purpose of this study was to identify the genetic pathogenesis of the "NKX2-1 triad" in a 10 year-old female presenting additional features barely described in the disorder. In the neonatal period, she presented with generalized hypotonia and respiratory distress, with later episodes of frequent wheezing. At 3 month-age developmental dysplasia of the hip was diagnosed and at 10 months, primary hypothyroidism was detected and treated...
February 22, 2018: European Journal of Medical Genetics
Cody A Phelps, Shao-Chiang Lai, David Mu
Thyroid transcription factor 1 (TTF-1 or NKX2-1) is a transcription factor of fundamental importance in driving lung maturation and morphogenesis. In the last decade, scientists began to appreciate the functional roles of TTF-1 in lung tumorigenesis. This movement was triggered by the discoveries of genetic alterations of TTF-1 in the form of gene amplification in lung cancer. Many downstream target genes of TTF-1 relevant to the lung cancer biology of TTF-1 have been documented. One of the most surprising findings was that TTF-1 may exhibit either pro- or antitumorigenic activities, an outcome with the complexity exceeding the original anticipation purely based on the fact that TTF-1 undergoes gene amplification in lung cancer...
2018: Vitamins and Hormones
Vincenzo Salpietro, Belen Perez-Dueñas, Kosuke Nakashima, Victoria San Antonio-Arce, Andreea Manole, Stephanie Efthymiou, Jana Vandrovcova, Conceicao Bettencourt, Niccolò E Mencacci, Christine Klein, Michy P Kelly, Ceri H Davies, Haruhide Kimura, Alfons Macaya, Henry Houlden
BACKGROUND: We investigated a family that presented with an infantile-onset chorea-predominant movement disorder, negative for NKX2-1, ADCY5, and PDE10A mutations. METHODS: Phenotypic characterization and trio whole-exome sequencing was carried out in the family. RESULTS: We identified a homozygous mutation affecting the GAF-B domain of the 3',5'-cyclic nucleotide phosphodiesterase PDE2A gene (c.1439A>G; p.Asp480Gly) as the candidate novel genetic cause of chorea in the proband...
February 2, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
Shawn Liang, Ellen Johansson, Guillermo Barila, Daniel L Altschuler, Henrik Fagman, Mikael Nilsson
The developmental program that regulates thyroid progenitor cell proliferation is largely unknown. Here we show that branching-like morphogenesis is a driving force to attain final size of the embryonic thyroid gland in mice. Sox9, a key factor in branching organ development, distinguishes Nkx2-1+ cells in the thyroid bud from progenitors originally forming the thyroid placode in anterior endoderm. As lobes develop the thyroid primordial tissue branches several generations. Sox9 and Fgfr2b are co-expressed distally in the branching epithelium prior to folliculogenesis...
December 22, 2017: Development
Jung Ran Choi, Sang-Baek Koh, Seong Yong Park, Hye Run Kim, Hyojin Lee, Dae Ryong Kang
Background: Lung cancer is the leading cause of cancer-related death worldwide, for which smoking is considered as the primary risk factor. The present study was conducted to determine whether genetic alterations induced by radon exposure are associated with the susceptible risk of lung cancer in never smokers. Methods: To accurately identify mutations within individual tumors, next generation sequencing was conduct for 19 pairs of lung cancer tissue. The associations of germline and somatic variations with radon exposure were visualized using OncoPrint and heatmap graphs...
December 2017: Journal of Cancer Prevention
Tadashi Shiohama, Hirofumi Ohashi, Kenji Shimizu, Katsunori Fujii, Daiju Oba, Tomozumi Takatani, Mitsuhiro Kato, Naoki Shimojo
Benign hereditary chorea (BHC) is a rare autosomal dominant disease that is characterized by non-progressive chorea with early-childhood-onset, congenital hypothyroidism, and neonatal respiratory distress. Although tetrabenazine and levodopa are partly effective for chorea and drop attacks in some patients, there is no standard treatment option. We herein describe a childhood case of BHC that presented with l-thyroxine-responsive drop attacks. A genetic analysis revealed an interstitial deletion that included two enhancer regions of NKX2-1, providing genetic confirmation of BHC...
December 27, 2017: Brain & Development
David J Tischfield, Stewart A Anderson
GABAergic cortical interneurons are a heterogeneous population of cells that play critical roles in regulating the output of excitatory pyramidal neurons as well as synchronizing the outputs of pyramidal neuron ensembles. Deficits in interneuron function have been implicated in a variety of neuropsychiatric disorders, including schizophrenia, autism, and epilepsy. The derivation of cortical interneurons from embryonic stem cells not only allows for the study of their development and function, but provides insight into the molecular mechanisms underlying the pathogenesis of cortical interneuron-related disorders...
December 3, 2017: Journal of Visualized Experiments: JoVE
Bing Chen, Lu Jiang, Meng-Ling Zhong, Jian-Feng Li, Ben-Shang Li, Li-Jun Peng, Yu-Ting Dai, Bo-Wen Cui, Tian-Qi Yan, Wei-Na Zhang, Xiang-Qin Weng, Yin-Yin Xie, Jing Lu, Rui-Bao Ren, Su-Ning Chen, Jian-Da Hu, De-Pei Wu, Zhu Chen, Jing-Yan Tang, Jin-Yan Huang, Jian-Qing Mi, Sai-Juan Chen
T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of immature T cells. Recently, the next-generation sequencing approach has allowed systematic identification of molecular features in pediatric T-ALL. Here, by performing RNA-sequencing and other genomewide analysis, we investigated the genomic landscape in 61 adult and 69 pediatric T-ALL cases. Thirty-six distinct gene fusion transcripts were identified, with SET-NUP214 being highly related to adult cases. Among 18 previously unknown fusions, ZBTB16-ABL1 , TRA-SALL2 , and involvement of NKX2-1 were recurrent events...
January 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
Mahima Tibrewal, Bokun Cheng, Preeti Dohare, Furong Hu, Rana Mehdizadeh, Ping Wang, Deyou Zheng, Zoltan Ungvari, Praveen Ballabh
Preterm-born children suffer from neurobehavioral disorders. Premature birth terminates the hypoxic in utero environment and supply of maternal hormones. As the production of interneurons continues until the end of pregnancy, we hypothesized that premature birth would disrupt interneuron production and restoration of the hypoxic milieu or estrogen treatment might reverse interneuron generation. To test these hypotheses, we quantified interneuronal progenitors in the medial, lateral, and caudal ganglionic eminences (MGE, LGE, and CGE) of preterm- (E29 at D3 and D7) vs...
December 15, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jorge Moisés, Alfons Navarro, Sandra Santasusagna, Nuria Viñolas, Laureano Molins, José Ramirez, Jeisson Osorio, Adela Saco, Joan Josep Castellano, Carmen Muñoz, Sara Morales, Mariano Monzó, Ramón María Marrades
BACKGROUND: NKX2-1, a key molecule in lung development, is highly expressed in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma (ADK), where it is a diagnostic marker. Studies of the prognostic role of NKX2-1 in NSCLC have reported contradictory findings. Two microRNAs (miRNAs) have been associated with NKX2-1: miR-365, which targets NKX2-1; and miR-33a, which is downstream of NKX2-1. We have examined the effect of NKX2-1, miR-365 and miR-33a on survival in a cohort of early-stage NSCLC patients and in sub-groups of patients classified according to the mutational status of TP53, KRAS, and EGFR...
December 13, 2017: BMC Pulmonary Medicine
Kesavan Meganathan, Emily M A Lewis, Paul Gontarz, Shaopeng Liu, Edouard G Stanley, Andrew G Elefanty, James E Huettner, Bo Zhang, Kristen L Kroll
Cortical interneurons (cINs) modulate excitatory neuronal activity by providing local inhibition. During fetal development, several cIN subtypes derive from the medial ganglionic eminence (MGE), a transient ventral telencephalic structure. While altered cIN development contributes to neurodevelopmental disorders, the inaccessibility of human fetal brain tissue during development has hampered efforts to define molecular networks controlling this process. Here, we modified protocols for directed differentiation of human embryonic stem cells, obtaining efficient, accelerated production of MGE-like progenitors and MGE-derived cIN subtypes with the expected electrophysiological properties...
December 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
Scott A Rankin, Kyle W McCracken, David M Luedeke, Lu Han, James M Wells, John M Shannon, Aaron M Zorn
A small number of signaling pathways are used repeatedly during organogenesis, and they can have drastically different effects on the same population of cells depending on the embryonic stage. How cellular competence changes over developmental time is not well understood. Here we used Xenopus, mouse, and human pluripotent stem cells to investigate how the temporal sequence of Wnt, BMP, and retinoic acid (RA) signals regulates endoderm developmental competence and organ induction, focusing on respiratory fate...
February 1, 2018: Developmental Biology
I C Nettore, S Desiderio, E De Nisco, V Cacace, L Albano, N Improda, P Ungaro, M Salerno, A Colao, P E Macchia
BACKGROUND: Congenital hypothyroidism is a frequent disease occurring with an incidence of about 1/1500 newborns/year. In about 75% of the cases, CH is caused by alterations in thyroid morphogenesis, defined "thyroid dysgenesis" (TD). TD is generally a sporadic disease but in about 5% of the cases a genetic origin has been demonstrated. Previous studies indicate that Dnajc17 as a candidate modifier gene for hypothyroidism, since it is expressed in the thyroid bud, interacts with NKX2...
November 20, 2017: Journal of Endocrinological Investigation
Poulomi Banerjee, Harshini Surendran, Kapil Bharti, Kaoru Morishita, Anurag Varshney, Rajarshi Pal
Early lung development is a tightly orchestrated process encompassing (a) formation of definitive endoderm, (b) anteriorization of definitive endoderm, followed by (c) specification and maturation of both proximal and distal lung precursors. Several reports detailing the interaction of genes and proteins during lung development are available; however, studies reporting the role(s) of long noncoding RNAs (lncRNA) in lung morphogenesis are limited. To investigate this, we tailored a protocol for differentiation of human-induced pluripotent stem cells into distal and proximal lung progenitors to mimic in vivo lung development...
February 2018: Stem Cells
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