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Gata4 Is Necessary for Normal Pulmonary Lobar Development

Division of Genetics, Brigham and Women's Hospital; Division of Emergency Medicine, Department of Medicine, and Division of Hematology and Oncology, Children's Hospital; Harvard Medical School; Howard Hughes Medical Institute; and Dana-Farber Cancer Institute, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Kate G. Ackerman, M.D., Division of Genetics, Brigham and Women's Hospital, Harvard Medical School New Research Building 458, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail: kackerman{at}rics.bwh.harvard.edu

Mutations of Fog2 in mice result in a phenotype that includes pulmonary lobar defects. To determine whether formation of the accessory lobe bronchus is mediated by a Gata family cofactor, we evaluated embryonic lungs from mice carrying missense mutations that cause loss of FOG–GATA protein interaction. Lungs from embryos carrying a missense mutation in Gata6 were structurally normal, while lungs from embryos carrying mutations of either Gata4 or of both Gata4 and Gata6 had a structural phenotype that matched the Fog2 mutant phenotype. Expression analysis showed that Gata4 and Fog2 are expressed in the ventral and medial pulmonary mesenchyme during secondary budding. Although Gata4 has not previously been suspected as playing a role in lung development, we have found that a Fog2–Gata4 interaction is critical for the development of normal pulmonary lobar structure, and this phenotype is not influenced by the additional loss of Gata6 interaction. Fog2 and Gata4 in the early pulmonary mesenchyme participate in patterning the secondary bronchus of the accessory lobe.

Key Words: lung • accessory lobe • Gata • Fog • branching

CLINICAL RELEVANCE We report that the transcription factor complex, FOG2-GATA4, mediates development of normal pulmonary lobar structure in mice. This establishes Gata4 as a transcription factor critical for early lung patterning.

 

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