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Anderson, William

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Anderson

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William

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Anderson, William
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    Notch signaling promotes airway mucous metaplasia and inhibits alveolar development
    (The Company of Biologists, 2009) Guseh, James; Bores, S. A.; Stanger, B. Z.; Zhou, Qiao; Anderson, William; Melton, Douglas; Rajagopal, Jayaraj
    The airways are conduits that transport atmospheric oxygen to the distal alveolus. Normally, airway mucous cells are rare. However, diseases of the airway are often characterized by mucous metaplasia, in which there are dramatic increases in mucous cell numbers. As the Notch pathway is known to regulate cell fate in many contexts, we misexpressed the active intracellular domain of the mouse Notch1 receptor in lung epithelium. Notch misexpression resulted in an increase in mucous cells and a decrease in ciliated cells in the airway. Similarly, mouse embryonic tracheal explants and adult human airway epithelium treated with Notch agonists displayed increased mucous cell numbers and decreased ciliated cell numbers. Notch antagonists had the opposite effect. Notably, Notch antagonists blocked IL13-induced mucous metaplasia. IL13 has a well-established role as an inflammatory mediator of mucous metaplasia and functions through Stat6-mediated gene transcription. We found that Notch ligands, however, are able to cause mucous metaplasia in Stat6-null cultured trachea, thus identifying a novel pathway that stimulates mucous metaplasia. Notch signaling may therefore play an important role in airway disease and, by extension, Notch antagonists may have therapeutic value. Conversely, in the distal lung, Notch misexpression prevented the differentiation of alveolar cell types. Instead, the distal lung formed cysts composed of cells that were devoid of alveolar markers but that expressed some, but not all, markers of proximal airway epithelium. Occasional distal cystic cells appeared to differentiate into normal proximal airway cells, suggesting that ectopic Notch signaling arrests the normal differentiation of distal lung progenitors before they initiate an alveolar program.
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    A Multipotent Progenitor Domain Guides Pancreatic Organogenesis
    (Elsevier BV, 2007) Zhou, Qiao; Law, Anica; Rajagopal, Jayaraj; Anderson, William; Gray, Paul A.; Melton, Douglas
    The mammalian pancreas is constructed during embryogenesis by multipotent progenitors, the identity and function of which remain poorly understood. We performed genome-wide transcription factor expression analysis of the developing pancreas to identify gene expression domains that may represent distinct progenitor cell populations. Five discrete domains were discovered. Genetic lineage-tracing experiments demonstrate that one specific domain, located at the tip of the branching pancreatic tree, contains multipotent progenitors that produce exocrine, endocrine, and duct cells in vivo. These multipotent progenitors are Pdx1+Ptf1a+cMycHighCpa1+ and negative for differentiated lineage markers. The outgrowth of multipotent tip cells leaves behind differentiated progeny that form the trunk of the branches. These findings define a multipotent compartment within the developing pancreas and suggest a model of how branching is coordinated with cell type specification. In addition, this comprehensive analysis of >1,100 transcription factors identified genes that are likely to control critical decisions in pancreas development and disease.
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    Creating Critical Consumers of Health and Science News: Teaching Science to the Non-Scientist Using Newsworthy Topics in the Life Sciences†
    (American Society of Microbiology, 2016) Coderre, Raymond W.; Uekermann, Kristen A.; Choi, Youngeun; Anderson, William
    Scientists constantly make groundbreaking discoveries, some of which receive attention from the press. We designed a course intended for a lay audience that provides the scientific background to appreciate these reports more fully. We discuss three topics in the life sciences: stem cells, cancer, and infectious disease. The course is structured to blend relevant scientific background and evaluation of primary literature with the coverage of these advances by the media and popular press. In short, lectures emphasize exposure to basic biological concepts and tools as a means of informing understanding of prominent biological questions of public interest. The overall goal of the course is not only to expose students to the media’s coverage of scientific progress, but also to hone their critical thinking skills to distinguish hope from hype.
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    Genetic Targeting of the Endoderm with Claudin-6CreER
    (Wiley-Blackwell, 2008) Anderson, William; Zhou, Qiao; Alcalde, Victor; Kaneko, Osamu F; Blank, Leah J; Sherwood, Richard; Guseh, James; Rajagopal, Jayaraj; Melton, Douglas
    A full description of the ontogeny of the β cell would guide efforts to generate β cells from embryonic stem cells (ESCs). The first step requires an understanding of definitive endoderm: the genes and signals responsible for its specification, proliferation, and patterning. This report describes a global marker of definitive endoderm, Claudin-6 (Cldn6). We report its expression in early development with particular attention to definitive endoderm derivatives. To create a genetic system to drive gene expression throughout the definitive endoderm with both spatial and temporal control, we target the endogenous locus with an inducible Cre recombinase (Cre-ERT2) cassette. Cldn6 null mice are viable and fertile with no obvious phenotypic abnormalities. We also report a lineage analysis of the fate of Cldn6-expressing embryonic cells, which is relevant to the development of the pancreas, lung, and liver.