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J. Biol. Chem., Vol. 283, Issue 30, 21160-21169, July 25, 2008

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Targeted Disruption of NeuroD, a Proneural Basic Helix-Loop-Helix Factor, Impairs Distal Lung Formation and Neuroendocrine Morphology in the Neonatal Lung^*

Enid R. Neptune¹, Megan Podowski, Carla Calvi, Jang-Hyeon Cho^¶, Joe G. N. Garcia, Rubin Tuder^||, R. Ilona Linnoila^**, Ming-Jer Tsai^¶, and Harry C. Dietz²

From the Division of Pulmonary and Critical Care Medicine, Institute of Genetic Medicine, Howard Hughes Medical Institute, ^||Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205, ^**Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, and the ^¶Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Despite the importance of airspace integrity in vertebrate gas exchange, the molecular pathways that instruct distal lung formation are poorly understood. Recently, we found that fibrillin-1 deficiency in mice impairs alveolar formation and recapitulates the pulmonary features of human Marfan syndrome. To further elucidate effectors involved in distal lung formation, we performed expression profiling analysis comparing the fibrillin-1-deficient and wild-type developing lung. NeuroD, a basic helix-loop-helix transcription factor, fulfilled the expression criteria for a candidate mediator of distal lung development. We investigated its role in murine lung development using genetically targeted NeuroD-deficient mice. We found that NeuroD deficiency results in both impaired alveolar septation and altered morphology of the pulmonary neuroendocrine cells. NeuroD-deficient mice had enlarged alveoli associated with reduced epithelial proliferation in the airway and airspace compartments during development. Additionally, the neuroendocrine compartment in these mice manifested an increased number of neuroepithelial bodies but a reduced number of solitary pulmonary neuroendocrine cells in the neonatal lung. Overexpression of NeuroD in a murine lung epithelial cell line conferred a neuroendocrine phenotype characterized by the induction of neuroendocrine markers as well as increased proliferation. These results support an unanticipated role for NeuroD in the regulation of pulmonary neuroendocrine and alveolar morphogenesis and suggest an intimate connection between the neuroendocrine compartment and distal lung development.

Received for publication, October 19, 2007 , and in revised form, February 12, 2008.

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^* This work was supported, in whole or in part, by National Institutes of Health Grants AR41135 (to H. D.), HL-69340 and KO8-HL067980 (to E. R. N.), DK 45641 and HD17379 (to M. J. T.), and RO1HL66554 (to R. M. T.), the Intramural Research Program (to R. I. L.), NCI (to R. I. L.), and U01 HL66583 (to J. G. N. G.). This research was also supported in part by the Howard Hughes Medical Institutes, William S. Smilow Center for Marfan Syndrome Research, and Center of Cancer Research (to R. I. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

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¹ To whom correspondence may be addressed: The Johns Hopkins University School of Medicine, 1830 E. Monument St., Rm. 547, Baltimore, MD 21205. Tel.: 443-287-3348; Fax: 410-955-0036; E-mail: eneptune{at}jhmi.edu.

² To whom correspondence may be addressed: The Johns Hopkins University School of Medicine, 733 N. Broadway, Rm. BRB539, Baltimore, MD 21205. Tel.: 410-614-0701; Fax: 410-614-2256; E-mail: hdietz{at}jhmi.edu.

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