HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 37, 35574-35583, September 12, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/37/35574    most recent M304885200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by deFelice, M. Articles by Whitsett, J. A. Search for Related Content PubMed PubMed Citation Articles by deFelice, M. Articles by Whitsett, J. A. Social Bookmarking                      What's this?

TTF-1 Phosphorylation Is Required for Peripheral Lung Morphogenesis, Perinatal Survival, and Tissue-specific Gene Expression^*

Mario deFelice , Daniel Silberschmidt , Roberto DiLauro , Yan Xu , Susan E. Wert , Timothy E. Weaver , Cindy J. Bachurski , Jean C. Clark  and Jeffrey A. Whitsett  ¶

From the Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039 and Stazione Zoologica "A. Dohrn," Villa Comunale, 80121 Naples, Italy

Thyroid transcription factor-1 (TTF-1) is a 43-kDa, phosphorylated member of the Nkx2 family of homeodomain-containing proteins expressed selectively in lung, thyroid, and the central nervous system. 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, Titf1^PM/PM, were generated by homologous recombination. Although heterozygous Titf1^PM/+ mice were unaffected, homozygous Titf1^PM/PM mice died immediately following birth. In contrast to Titf1 null mutant mice, which lack peripheral lung tissues, bronchiolar and peripheral acinar components of the lung were present in the Titf1^PM/PM mice. Although lobulation and early branching morphogenesis were maintained in the mutant mice, abnormalities in acinar tubules and pulmonary hypoplasia indicated defects in lung morphogenesis later in development. Although TTF-1^PM protein was readily detected within the nuclei of pulmonary epithelial cells at sites and abundance consistent with that of endogenous TTF-1, expression of a number of known TTF-1 target genes, including surfactant proteins and secretoglobulin 1A, was variably decreased in the mutant mice. Vascular endothelial growth factor mRNA was decreased in association with decreased formation of peripheral pulmonary blood vessels. Genes mediating surfactant homeostasis, vasculogenesis, host defense, fluid homeostasis, and inflammation were highly represented among those regulated by TTF-1. Thus, in contrast to the null Titf1 mutation, the Titf1^PM/PM mutant substantially restored lung morphogenesis. Direct and indirect transcriptional targets of TTF-1 were identified that are likely to play important roles in lung formation and function.

Received for publication, May 9, 2003 , and in revised form, June 20, 2003.

^* This work was supported by National Institutes of Health Grants HL56387 and HL38859 (to J. A. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Cincinnati Children's Hospital Medical Center, Divisions of Neonatology and Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Tel.: 513-636-4830; Fax: 513-636-7868; E-mail: jeff.whitsett{at}cchmc.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. S. W. Ngan, B. H. H. Lang, T. Liu, C. K. Y. Shum, M.-T. So, D. K. C. Lau, T. Y. Y. Leon, S. S. Cherny, S. Y. Tsai, C.-Y. Lo, 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, February 4, 2009; 101(3): 162 - 175. [Abstract] [Full Text] [PDF]

				E. Maquet, S. Costagliola, J. Parma, C. Christophe-Hobertus, L. L. Oligny, J.-C. Fournet, Y. Robitaille, J.-M. Vuissoz, A. Payot, S. Laberge, et al. Lethal Respiratory Failure and Mild Primary Hypothyroidism in a Term Girl with a de Novo Heterozygous Mutation in the TITF1/NKX2.1 Gene J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 197 - 203. [Abstract] [Full Text] [PDF]

				Y. Saini, J. R. Harkema, and J. J. LaPres HIF1{alpha} Is Essential for Normal Intrauterine Differentiation of Alveolar Epithelium and Surfactant Production in the Newborn Lung of Mice J. Biol. Chem., November 28, 2008; 283(48): 33650 - 33657. [Abstract] [Full Text] [PDF]

				W. V. Cardoso and J. A. Whitsett Resident Cellular Components of the Lung: Developmental Aspects Proceedings of the ATS, September 15, 2008; 5(7): 767 - 771. [Abstract] [Full Text] [PDF]

				H. Wan, F. Luo, S. E. Wert, L. Zhang, Y. Xu, M. Ikegami, Y. Maeda, S. M. Bell, and J. A. Whitsett Kruppel-like factor 5 is required for perinatal lung morphogenesis and function Development, August 1, 2008; 135(15): 2563 - 2572. [Abstract] [Full Text] [PDF]

				V. Besnard, Y. Xu, and J. A. Whitsett Sterol response element binding protein and thyroid transcription factor-1 (Nkx2.1) regulate Abca3 gene expression Am J Physiol Lung Cell Mol Physiol, December 1, 2007; 293(6): L1395 - L1405. [Abstract] [Full Text] [PDF]

				J. Kendall, Q. Liu, A. Bakleh, A. Krasnitz, K. C. Q. Nguyen, B. Lakshmi, W. L. Gerald, S. Powers, and D. Mu Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer PNAS, October 16, 2007; 104(42): 16663 - 16668. [Abstract] [Full Text] [PDF]

				J. G. Kim, Y. J. Son, C. H. Yun, Y. I. Kim, I. S. Nam-goong, J. H. Park, S. K. Park, S. R. Ojeda, A. V. D'Elia, G. Damante, et al. Thyroid Transcription Factor-1 Facilitates Cerebrospinal Fluid Formation by Regulating Aquaporin-1 Synthesis in the Brain J. Biol. Chem., May 18, 2007; 282(20): 14923 - 14931. [Abstract] [Full Text] [PDF]

				V. Kolla, L. W. Gonzales, J. Gonzales, P. Wang, S. Angampalli, S. I. Feinstein, and P. L. Ballard Thyroid Transcription Factor in Differentiating Type II Cells: Regulation, Isoforms, and Target Genes Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 213 - 225. [Abstract] [Full Text] [PDF]

				M. T. Stahlman, V. Besnard, S. E. Wert, T. E. Weaver, S. Dingle, Y. Xu, K. von Zychlin, S. J. Olson, and J. A. Whitsett Expression of ABCA3 in Developing Lung and Other Tissues J. Histochem. Cytochem., January 1, 2007; 55(1): 71 - 83. [Abstract] [Full Text] [PDF]

				Y. Maeda, V. Dave, and J. A. Whitsett Transcriptional Control of Lung Morphogenesis Physiol Rev, January 1, 2007; 87(1): 219 - 244. [Abstract] [Full Text] [PDF]

				J. Xu, J. Tian, S. M. Grumelli, K. J. Haley, and S. D. Shapiro Stage-specific Effects of cAMP Signaling during Distal Lung Epithelial Development J. Biol. Chem., December 15, 2006; 281(50): 38894 - 38904. [Abstract] [Full Text] [PDF]

				S. Lin, A.-K. T. Perl, and J. M. Shannon Erm/Thyroid Transcription Factor 1 Interactions Modulate Surfactant Protein C Transcription J. Biol. Chem., June 16, 2006; 281(24): 16716 - 16726. [Abstract] [Full Text] [PDF]

				K. C. Wade, S. H. Guttentag, L. W. Gonzales, K. L. Maschhoff, J. Gonzales, V. Kolla, S. Singhal, and P. L. Ballard Gene Induction during Differentiation of Human Pulmonary Type II Cells In Vitro Am. J. Respir. Cell Mol. Biol., June 1, 2006; 34(6): 727 - 737. [Abstract] [Full Text] [PDF]

				Y. Maeda, T. C. Hunter, D. E. Loudy, V. Dave, V. Schreiber, and J. A. Whitsett PARP-2 Interacts with TTF-1 and Regulates Expression of Surfactant Protein-B J. Biol. Chem., April 7, 2006; 281(14): 9600 - 9606. [Abstract] [Full Text] [PDF]

				P. C. Martis, J. A. Whitsett, Y. Xu, A.-K. T. Perl, H. Wan, and M. Ikegami C/EBP{alpha} is required for lung maturation at birth Development, March 15, 2006; 133(6): 1155 - 1164. [Abstract] [Full Text] [PDF]

				J. P. Bridges, Y. Xu, C.-L. Na, H. R. Wong, and T. E. Weaver Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C J. Cell Biol., January 30, 2006; 172(3): 395 - 407. [Abstract] [Full Text] [PDF]

				A.-K. T. Perl, S. E. Wert, D. E. Loudy, Z. Shan, P. A. Blair, and J. A. Whitsett Conditional Recombination Reveals Distinct Subsets of Epithelial Cells in Trachea, Bronchi, and Alveoli Am. J. Respir. Cell Mol. Biol., November 1, 2005; 33(5): 455 - 462. [Abstract] [Full Text] [PDF]

				H. Wan, S. Dingle, Y. Xu, V. Besnard, K. H. Kaestner, S.-L. Ang, S. Wert, M. T. Stahlman, and J. A. Whitsett Compensatory Roles of Foxa1 and Foxa2 during Lung Morphogenesis J. Biol. Chem., April 8, 2005; 280(14): 13809 - 13816. [Abstract] [Full Text] [PDF]

				H. Wan, Y. Xu, M. Ikegami, M. T. Stahlman, K. H. Kaestner, S.-L. Ang, and J. A. Whitsett Foxa2 is required for transition to air breathing at birth PNAS, October 5, 2004; 101(40): 14449 - 14454. [Abstract] [Full Text] [PDF]

				P. R. Reynolds, M. L. Mucenski, T. D. Le Cras, W. C. Nichols, and J. A. Whitsett Midkine Is Regulated by Hypoxia and Causes Pulmonary Vascular Remodeling J. Biol. Chem., August 27, 2004; 279(35): 37124 - 37132. [Abstract] [Full Text] [PDF]

				V. Dave, T. Childs, and J. A. Whitsett 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., August 13, 2004; 279(33): 34578 - 34588. [Abstract] [Full Text] [PDF]

				J. A. Whitsett, C. J. Bachurski, K. C. Barnes, P. A. Bunn Jr., L. M. Case, D. N. Cook, D. Crooks, M. W. Duncan, L. Dwyer-Nield, R. C. Elston, et al. Functional Genomics of Lung Disease Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2/S1): S1 - S81. [Full Text] [PDF]

				M. Rova, R. Haataja, R. Marttila, V. Ollikainen, O. Tammela, and M. Hallman Data mining and multiparameter analysis of lung surfactant protein genes in bronchopulmonary dysplasia Hum. Mol. Genet., June 1, 2004; 13(11): 1095 - 1104. [Abstract] [Full Text] [PDF]

				K.-S. Park, J. A. Whitsett, T. Di Palma, J.-H. Hong, M. B. Yaffe, and M. Zannini TAZ Interacts with TTF-1 and Regulates Expression of Surfactant Protein-C J. Biol. Chem., April 23, 2004; 279(17): 17384 - 17390. [Abstract] [Full Text] [PDF]

				T. Ueno, S. Linder, C.-L. Na, W. R. Rice, J. Johansson, and T. E. Weaver Processing of Pulmonary Surfactant Protein B by Napsin and Cathepsin H J. Biol. Chem., April 16, 2004; 279(16): 16178 - 16184. [Abstract] [Full Text] [PDF]