The Transcription Factor Gene Nfib Is Essential for both Lung Maturation and Brain Development

Abstract

The phylogenetically conserved nuclear factor I (NFI) gene family encodes site-specific transcription factors essential for the development of a number of organ systems. We showed previously that Nfia-deficient mice exhibit agenesis of the corpus callosum and other forebrain defects, whereas Nfic-deficient mice have agenesis of molar tooth roots and severe incisor defects. Here we show that Nfib-deficient mice possess unique defects in lung maturation and exhibit callosal agenesis and forebrain defects that are similar to, but more severe than, those seen in Nfia-deficient animals. In addition, loss of Nfib results in defects in basilar pons formation and hippocampus development that are not seen in Nfia-deficient mice. Heterozygous Nfib-deficient animals also exhibit callosal agenesis and delayed lung maturation, indicating haploinsufficiency at the Nfib locus. The similarity in brain defects in Nfia- and Nfib-deficient animals suggests that these two genes may cooperate in late fetal forebrain development, while Nfib is essential for late fetal lung maturation and development of the pons.

ACKNOWLEDGMENTS

We thank Valerie Stewart of the Cleveland Clinic Transgenic/Knockout facility for blastocyst injections and the generation of founder chimeras and Clemencia Colmenares (Cleveland Clinic) for advise and assistance in ES cell culture. We also thank Kimberly Valentino and Rebecca Pacifico (UMB) for excellent technical assistance and Christine E. Campbell (SUNY-Buffalo) for reading the manuscript and helpful discussions.

This work was supported in part by Public Health Service grants HD34901 from the National Institute of Child Health and Development and DK58401 and DK48796 from the National Institute of Diabetes and Digestive and Kidney Diseases to R.M.G. and HL60907 from the National Heart, Lung and Blood Institute to C.J.B.