The Chuang Lab
Defective lung branching in Rptor-deficient mouse lungs due to loss of mTORC1 signaling
Lung branching morphogenesis
We have chosen lung branching in mice as a model to understand how multiple signals are integrated to make a tissue or organ. With the availability of ex vivo organ culture, the stereotyped branching patterns and the molecular and genetic tools, the lung is an attractive system to address the molecular mechanisms of branching morphogenesis and cell type specification.
Key Publications:
Zhang K, Yao E, Chuang E, Chen B, Chuang EY, Volk RF, Hofmann KL, Zaro B, Chuang PT. Wnt5a-Vangl1/2 signaling regulates the position and direction of lung branching through the cytoskeleton and focal adhesions. PLoS Biol. 2022 Aug 26;20(8):e3001759.
Lin C, Yao E, Zhang K, Jiang X, Croll S, Thompson-Peer K, Chuang PT. 2017. YAP is essential for mechanical force production and epithelial cell proliferation during lung branching morphogenesis Elife. 2017 Mar 21;6. pii: e21130.
Lin C, Chen MH, Yao E, Song H, Gacayan R, Hui CC, Chuang PT. Differential regulation of Gli proteins by Sufu in the lung affects PDGF signaling and myofibroblast development. Dev Biol. 2014 Aug 15;392(2):324-33. doi: 10.1016/j.ydbio.2014.05.014. Epub 2014 Jun 2. PMID: 24886827; PMCID: PMC4106470.
Lin C, Chen M-H, Yao E, Song H, Gacayan R, Hui CC, Chuang, PT. 2014. Differential regulation of Gli proteins by Sufu in the lung affects PDGF signaling and myofibroblast development. Dev Biol 392(2):324-33.
Chuang P.-T.*, Kawcak T., McMahon A.P. 2003. Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding Protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung. Genes Dev 17(3):342-7. (*co-corresponding author)
Loss of alveoli in lungs of COPD patients
Alveolar formation
We investigate the molecular basis of alveolar formation.The alveolus, the unit of gas exchange, is produced during the last phase of lung development. Formation of alveoli greatly increases the surface area and efficiency of gas exchange, enabling high activity in terrestrial environments. Loss of alveoli underlies many human diseases including chronic obstructive lung disease (COPD).
Key Publications:
Zhang K, Yao E, Wang SA, Chuang E, Wong J, Minichiello L, Schroeder A, Eckalbar W, Wolters PJ, Chuang PT. A functional circuit formed by the autonomic nerves and myofibroblasts controls mammalian alveolar formation for gas exchange. Dev Cell. 2022 Jul 11;57(13):1566-1581.e7.
Zhang K, Yao E, Chen B, Chuang E, Wong J, Seed RI, Nishimura SL, Wolters PJ, Chuang PT. Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria. Elife. 2022 Apr 6;11:e68598.
Zhang K, Yao E, Lin C, Chou YT, Wong J, Li J, Wolters PJ, Chuang PT. A mammalian Wnt5a-Ror2-Vangl2 axis controls the cytoskeleton and confers cellular properties required for alveologenesis. Elife. 2020 May 12;9:e53688.
Transdifferentiation of pulmonary neuroendocrine cells in response to lung injury
Lung repair and regeneration
Lungs exhibit remarkable regenerative potential in response to various types of injuries. We employ the mouse as a model system to investigate the molecular pathways that regulate airway and alveolar repair/regeneration. This approach is complemented by studies aimed to test the function of these pathways in human lung cells.
Key Publications:
Yao E, Lin C, Wu Q, Zhang K, Song H, Chuang PT. Notch Signaling Controls Transdifferentiation of Pulmonary Neuroendocrine Cells in Response to Lung Injury. Stem Cells. 2018 Mar;36(3):377-391
Development of lung tumors by manipulating p53 and Kras activities in alveolar epithelial cell
Lung cancer
Lung cancer has the highest mortality rate among all cancers and continues to be a major threat to human health. We use mouse models of lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), to address several key issues in lung cancer. We aim to uncover the cells of origin of lung cancer, reveal the molecular pathways that control cancer development, and identify driver mutations responsible for tumor initiation, progression, metastasis, and resistance to therapies. Next-generation sequencing of human lung cancer has yielded a large number of potential driver mutations. Mouse models of lung cancer provide an important means to functionally test driver mutations in a signaling network.
Lin C, Song H, Huang C, Yao E, Gacayan R, Xu SM, Chuang, PT. 2012. Alveolar Type II Cells Possess the Capability of Initiating Lung Tumor Development. PLoS ONE 7(12): e53817. Epub 2012 Dec 20.
Song H, Yao E, Lin C, Gacayan R, Chen MH, Chuang PT. 2012 Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis. Proc Natl Acad Sci U S A. 2012 Oct 23; 109(43):17531-6.
Disruption of basal foot orientation in motile cilia of Fu-deficient mouse trachea
Restoration of ciliary localization of GLI2 and GLI3 in Sufu-deficient MEFs by mouse or Drosophila SUFU
Mammalian Hedgehog signaling in embryonic development and postnatal physiology
We study the molecular mechanisms of Hedgehog (Hh) signaling in mammalian development and physiology using the mouse as a model system. The Hh pathway plays an essential role in many aspects of embryonic development and dysfunction of Hh signaling is associated with human congenital anomalies and cancers. A combination of mouse genetics, genomic analysis, cell biology, and biochemistry is utilized to answer the major question of how graded outputs are generated in response to a Hh gradient. In particular, we focus on how the three Gli transcription factors mediate Hh responses in a given tissue.
Lin C, Yao E, Wang K, Nozawa Y, Shimizu H, Johnson JR, Chen JN, Krogan NJ, Chuang PT. 2014. Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling. Genes Dev 28(22):2547-63.
Chen M.-H., Wilson C.W., Li Y.-J., Law K.K., Lu C.-S., Gacayan R., Zhang X., Hui C.-c., Chuang P.-T. 2009. Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev 23(16):1910-28. Faculty of 1000 Biology
Wilson C.W., Chen M.-H., Chuang P.-T. 2009. Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PLoS ONE 4(4):e5182. Epub 2009 April 13.
Wilson C.W., Nguyen C., Chen M.-H., Yang J.-H., Gacayan R., Chen J.-N., Chuang P.-T. 2009. Fused has evolved divergent roles in vertebrate Hedgehog signaling and motile ciliogenesis. Nature 459 (7243):98-102. Epub 2009 Mar 22. Faculty of 1000 Medicine
Chen M.-H., Gao N., Kawakami T., Chuang P.-T. 2005. Mice deficient in the Fused homolog do not exhibit phenotypes indicative of perturbed Hedgehog signaling during embryonic development. Mol Cell Biol 25(16):7042-53
Chen M.-H., Li Y.-J., Kawakami T., Xu S.-M., Chuang P.-T. 2004. Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev 18(6):641-59. Faculty of 1000 Biology
Kawakami T., Kawcak T., Li Y.-J., Zhang W., Hu Y., Chuang P.-T. 2002. Mouse dispatched mutants fail to distribute Hedgehog proteins and are defective in Hedgehog signaling. Development 129(24):5753-65.