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Forkhead Box m1 transcription factor is required for perinatal lung function.

ABSTRACT: The Forkhead Box m1 (Foxm1 or Foxm1b) transcription factor (previously called HFH-11B, Trident, Win, or MPP2) is an important positive regulator of DNA replication and mitosis in a variety of cell types. Global deletion of Foxm1 in Foxm1(-/-) mice is lethal in the embryonic period, causing multiple abnormalities in the liver, heart, lung, and blood vessels. In the present study, Foxm1 was deleted conditionally in the respiratory epithelium (epFoxm1(-/-)). Surprisingly, deletion of Foxm1 did not alter lung growth, branching morphogenesis, or epithelial proliferation but inhibited lung maturation and caused respiratory failure after birth. Maturation defects in epFoxm1(-/-) lungs were associated with decreased expression of T1-alpha and aquaporin 5, consistent with a delay of type I cell differentiation. Expression of surfactant-associated proteins A, B, C, and D was decreased by deletion of Foxm1. Foxm1 directly bound and induced transcriptional activity of the mouse surfactant protein B and A (Sftpb and Sftpa) promoters in vitro, indicating that Foxm1 is a direct transcriptional activator of these genes. Foxm1 is critical for surfactant homeostasis and lung maturation before birth and is required for adaptation to air breathing.

SUBMITTER: Kalin TV

PROVIDER: S-EPMC2587228 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:FoxD4L1 is a forkhead transcription factor that expands the neural ectoderm by down-regulating genes that promote the onset of neural differentiation and up-regulating genes that maintain proliferative neural precursors in an immature state. We previously demonstrated that binding of Grg4 to an Eh-1 motif enhances the ability of FoxD4L1 to down-regulate target neural genes but does not account for all of its repressive activity. Herein we analyzed the protein sequence for additional interaction motifs and secondary structure. Eight conserved motifs were identified in the C-terminal region of fish and frog proteins. Extending the analysis to mammals identified a high scoring motif downstream of the Eh-1 domain that contains a tryptophan residue implicated in protein-protein interactions. In addition, secondary structure prediction programs predicted an ?-helical structure overlapping with amphibian-specific Motif 6 in Xenopus, and similarly located ?-helical structures in other vertebrate FoxD proteins. We tested functionality of this site by inducing a glutamine-to-proline substitution expected to break the predicted ?-helical structure; this significantly reduced FoxD4L1's ability to repress zic3 and irx1. Because this mutation does not interfere with Grg4 binding, these results demonstrate that at least two regions, the Eh-1 motif and a more C-terminal predicted ?-helical/Motif 6 site, additively contribute to repression. In the N-terminal region we previously identified a 14 amino acid motif that is required for the up-regulation of target genes. Secondary structure prediction programs predicted a short ?-strand separating two acidic domains. Mutant constructs show that the ?-strand itself is not required for transcriptional activation. Instead, activation depends upon a glycine residue that is predicted to provide sufficient flexibility to bring the two acidic domains into close proximity. These results identify conserved predicted motifs with secondary structures that enable FoxD4L1 to carry out its essential functions as both a transcriptional repressor and activator of neural genes.

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Forkhead Box m1 transcription factor is required for perinatal lung function.

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