Lung epithelial development is transcriptionally controlled through both positive and negative regulators. Amongst these regulators, the forkhead/winged helix family or Fox family of DMA binding proteins play a central role. Our previous studies have demonstrated that Foxp1/2/4 are potent transcriptional repressors of lung gene transcription and each gene is expressed in overlapping patterns in lung epithelia. We have shown that mouse knock-out models of each of these genes demonstrate unique roles in lung, cardiac, and neural development. In the lung, Foxp2 regulates postnatal alveolarization in part through direct regulation of the alveolar epithelial type 1 cell (AEC-1) gene T1 alpha. In addition to their individual roles in development, recent evidence from our laboratory has demonstrated that Foxp1 and Foxp2 regulate lung airway morphogenesis in a compensatory manner. Foxp1/2/4 are transcriptional repressors and we have demonstrated that these factors link chromatin remodeling to target promoters through interactions with p66, a component of the NuRD (nucleosome remodeling histone deacetylase) complex. Transcriptional repression through complexes such as NuRD and their components including HDAC2 (histone deacetylase 2) are important for surfactant protein gene expression and lung epithelial maturation as our recent data on HDAC2 and the interacting homeodomain only protein (HOP) indicate. These findings demonstrate that Foxp1/2/4 play critical roles in regulation of lung epithelial specific genes, which are required for airway development and postnatal lung homeostasis. However, little is known about whether these factors act redundantly/cooperatively to regulate transcriptional targets in the lung, the mechanism of how Foxp1/2/4 repress lung gene transcription and the effect that loss of these factors has on activation and differentiation of airway progenitor cells including bronchioalveolar stem cells (BASCs) after lung injury. These questions will be addressed in the specific aims of this proposal.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Blaisdell, Carol J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Li, Shanru; Koziol-White, Cynthia; Jude, Joseph et al. (2016) Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness. J Clin Invest 126:1978-82
Li, Shanru; Morley, Michael; Lu, MinMin et al. (2016) Foxp transcription factors suppress a non-pulmonary gene expression program to permit proper lung development. Dev Biol 416:338-46
Spaeth, Jason M; Hunter, Chad S; Bonatakis, Lauren et al. (2015) The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice. Diabetologia 58:1836-44
Snitow, Melinda E; Li, Shanru; Morley, Michael P et al. (2015) Ezh2 represses the basal cell lineage during lung endoderm development. Development 142:108-17
Herriges, Michael; Morrisey, Edward E (2014) Lung development: orchestrating the generation and regeneration of a complex organ. Development 141:502-13
Hogan, Brigid L M; Barkauskas, Christina E; Chapman, Harold A et al. (2014) Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15:123-38
Wang, Yi; Tian, Ying; Morley, Michael P et al. (2013) Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway. Dev Cell 24:345-58
Li, Shanru; Wang, Yi; Zhang, Yuzhen et al. (2012) Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2. Development 139:2500-9
Rousso, David L; Pearson, Caroline Alayne; Gaber, Zachary B et al. (2012) Foxp-mediated suppression of N-cadherin regulates neuroepithelial character and progenitor maintenance in the CNS. Neuron 74:314-30
Wiehagen, Karla R; Corbo-Rodgers, Evann; Li, Shanru et al. (2012) Foxp4 is dispensable for T cell development, but required for robust recall responses. PLoS One 7:e42273

Showing the most recent 10 out of 24 publications