This Article Full Text Full Text (PDF) All Versions of this Article: 2006-0207OCv1 36/2/213    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kolla, V. Articles by Ballard, P. L. Search for Related Content PubMed PubMed Citation Articles by Kolla, V. Articles by Ballard, P. L.

Thyroid Transcription Factor in Differentiating Type II Cells

Regulation, Isoforms, and Target Genes

Department of Pediatrics, Division of Neonatology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, and Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Philip L. Ballard, M.D., Ph.D., University of California San Francisco, 3333 California St., Suite 150, San Francisco, CA 94118-1981. E-mail: ballardp{at}peds.ucsf.edu

Thyroid transcription factor-1 (TTF-1, product of the Nkx2.1 gene) is essential for branching morphogenesis of the lung and enhances expression of surfactant proteins by alveolar type II cells. We investigated expression of two TTF-1 mRNA transcripts, generated by alternative start sites and coding for 42- and 46-kD protein isoforms in the mouse, during hormone-induced differentiation of human fetal lung type II cells in culture. Transcript for 42-kD TTF-1 was 20-fold more abundant than TTF-1₄₆ mRNA by RT-PCR. Only 42-kD protein was detected in lung cells, and its content increased during in vivo development and in response to in vitro glucocorticoid plus cAMP treatment. To examine TTF-1 target proteins, recombinant, phosphorylated TTF-1₄₂ was expressed in nuclei of cells by adenovirus transduction. By microarray analysis, 14 genes were comparably induced by recombinant TTF-1 (rTTF-1) and hormone treatment, and 9 additional hormone-responsive genes, including surfactant proteins-A/B/C, were partially induced by rTTF-1. The most highly ( 10-fold) TTF-1–induced genes were DC-LAMP (LAMP3) and CEACAM6 with induction confirmed by Western analysis and immunostaining. Treatment of cells with hormones plus small inhibitory RNA directed toward TTF-1 reduced TTF-1 content by 50% and inhibited hormone induction of the 23 genes induced by rTTF-1. 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.

Key Words: cyclic AMP • dexamethasone • gene expression • microarray • surfactant protein B

This article has been cited by other articles:

				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]