Publications by authors named "Lucy X Morris"

7 Publications

  • Page 1 of 1

NINJ1 mediates plasma membrane rupture during lytic cell death.

Nature 2021 Mar 20;591(7848):131-136. Epub 2021 Jan 20.

Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA, USA.

Plasma membrane rupture (PMR) is the final cataclysmic event in lytic cell death. PMR releases intracellular molecules known as damage-associated molecular patterns (DAMPs) that propagate the inflammatory response. The underlying mechanism of PMR, however, is unknown. Here we show that the cell-surface NINJ1 protein, which contains two transmembrane regions, has an essential role in the induction of PMR. A forward-genetic screen of randomly mutagenized mice linked NINJ1 to PMR. Ninj1 macrophages exhibited impaired PMR in response to diverse inducers of pyroptotic, necrotic and apoptotic cell death, and were unable to release numerous intracellular proteins including HMGB1 (a known DAMP) and LDH (a standard measure of PMR). Ninj1 macrophages died, but with a distinctive and persistent ballooned morphology, attributable to defective disintegration of bubble-like herniations. Ninj1 mice were more susceptible than wild-type mice to infection with Citrobacter rodentium, which suggests a role for PMR in anti-bacterial host defence. Mechanistically, NINJ1 used an evolutionarily conserved extracellular domain for oligomerization and subsequent PMR. The discovery of NINJ1 as a mediator of PMR overturns the long-held idea that cell death-related PMR is a passive event.
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http://dx.doi.org/10.1038/s41586-021-03218-7DOI Listing
March 2021

IRF2 transcriptionally induces expression for pyroptosis.

Sci Signal 2019 05 21;12(582). Epub 2019 May 21.

Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.

Gasdermin-D (GSDMD) is cleaved by caspase-1, caspase-4, and caspase-11 in response to canonical and noncanonical inflammasome activation. Upon cleavage, GSDMD oligomerizes and forms plasma membrane pores, resulting in interleukin-1β (IL-1β) secretion, pyroptotic cell death, and inflammatory pathologies, including periodic fever syndromes and septic shock-a plague on modern medicine. Here, we showed that IRF2, a member of the interferon regulatory factor (IRF) family of transcription factors, was essential for the transcriptional activation of A forward genetic screen with -ethyl--nitrosourea (ENU)-mutagenized mice linked IRF2 to inflammasome signaling. expression was substantially attenuated in deficient macrophages, endothelial cells, and multiple tissues, which corresponded with reduced IL-1β secretion and inhibited pyroptosis. Mechanistically, IRF2 bound to a previously uncharacterized but unique site within the promoter to directly drive transcription for the execution of pyroptosis. Disruption of this single IRF2-binding site abolished signaling by both the canonical and noncanonical inflammasomes. Together, our data illuminate a key transcriptional mechanism for expression of the gene encoding GSDMD, a critical mediator of inflammatory pathologies.
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http://dx.doi.org/10.1126/scisignal.aax4917DOI Listing
May 2019

Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.

Nature 2015 Oct 16;526(7575):666-71. Epub 2015 Sep 16.

Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA.

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1β processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1β maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1β secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-/-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.
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http://dx.doi.org/10.1038/nature15541DOI Listing
October 2015

Dynamics of thymus organogenesis and colonization in early human development.

Development 2013 May;140(9):2015-26

MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, CRM Building, 5 Little France Drive, Edinburgh..

The thymus is the central site of T-cell development and thus is of fundamental importance to the immune system, but little information exists regarding molecular regulation of thymus development in humans. Here we demonstrate, via spatial and temporal expression analyses, that the genetic mechanisms known to regulate mouse thymus organogenesis are conserved in humans. In addition, we provide molecular evidence that the human thymic epithelium derives solely from the third pharyngeal pouch, as in the mouse, in contrast to previous suggestions. Finally, we define the timing of onset of hematopoietic cell colonization and epithelial cell differentiation in the human thymic primordium, showing, unexpectedly, that the first colonizing hematopoietic cells are CD45(+)CD34(int/-). Collectively, our data provide essential information for translation of principles established in the mouse to the human, and are of particular relevance to development of improved strategies for enhancing immune reconstitution in patients.
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http://dx.doi.org/10.1242/dev.087320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631974PMC
May 2013

Steroid signaling within Drosophila ovarian epithelial cells sex-specifically modulates early germ cell development and meiotic entry.

PLoS One 2012 2;7(10):e46109. Epub 2012 Oct 2.

Howard Hughes Medical Institute, Department of Embryology, Carnegie Institution, Baltimore, Maryland, United States of America.

Drosophila adult females but not males contain high levels of the steroid hormone ecdysone, however, the roles played by steroid signaling during Drosophila gametogenesis remain poorly understood. Drosophila germ cells in both sexes initially follow a similar pathway. After germline stem cells are established, their daughters form interconnected cysts surrounded by somatic escort (female) or cyst (male) cells and enter meiosis. Subsequently, female cysts acquire a new covering of somatic cells to form follicles. Knocking down expression of the heterodimeric ecdysteroid receptor (EcR/Usp) or the E75 early response gene in escort cells disrupts 16-cell cyst production, meiotic entry and follicle formation. Escort cells lose their squamous morphology and unsheath germ cells. By contrast, disrupting ecdysone signaling in males does not perturb cyst development or ensheathment. Thus, sex-specific steroid signaling is essential for female germ cell development at the time male and female pathways diverge. Our results suggest that steroid signaling plays an important sex-specific role in early germ cell development in Drosophila, a strategy that may be conserved in mammals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046109PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462805PMC
April 2013

Drosophila stem cell niches: a decade of discovery suggests a unified view of stem cell regulation.

Dev Cell 2011 Jul;21(1):159-71

Howard Hughes Medical Institute Research Laboratories, Department of Embryology, Carnegie Institution for Science, 3520 San Martin Drive, Baltimore, MD 21218, USA.

The past decade of research on Drosophila stem cells and niches has provided key insights. Fly stem cells do not occupy a special "state" based on novel "stem cell genes" but resemble transiently arrested tissue progenitors. Moreover, individual stem cells and downstream progenitors are highly dynamic and dispensable, not tissue bulwarks. Niches, rather than fixed cell lineages, ensure tissue health by holding stem cells and repressing cell differentiation inside, but not outside. We review the five best-understood adult Drosophila stem cells and argue that the fundamental biology of stem cells and niches is conserved between Drosophila and mice.
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http://dx.doi.org/10.1016/j.devcel.2011.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894370PMC
July 2011

Long-term live imaging provides new insight into stem cell regulation and germline-soma coordination in the Drosophila ovary.

Development 2011 Jun;138(11):2207-15

Howard Hughes Medical Institute, Department of Embryology, Carnegie Institution, 3520 San Martin Drive, Baltimore, MD 21218, USA.

The Drosophila ovariole tip produces new ovarian follicles on a 12-hour cycle by controlling niche-based germline and follicle stem cell divisions and nurturing their developing daughters. Static images provide a thumbnail view of folliculogenesis but imperfectly capture the dynamic cellular interactions that underlie follicle production. We describe a live-imaging culture system that supports normal ovarian stem cell activity, cyst movement and intercellular interaction over 14 hours, which is long enough to visualize all the steps of follicle generation. Our results show that live imaging has unique potential to address diverse aspects of stem cell biology and gametogenesis. Stem cells in cultured tissue respond to insulin and orient their mitotic spindles. Somatic escort cells, the glial-like partners of early germ cells, do not adhere to and migrate along with germline stem cell daughters as previously proposed. Instead, dynamic, microtubule-rich cell membranes pass cysts from one escort cell to the next. Additionally, escort cells are not replenished by the regular division of escort stem cells as previously suggested. Rather, escort cells remain quiescent and divide only to maintain a constant germ cell:escort cell ratio.
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http://dx.doi.org/10.1242/dev.065508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091492PMC
June 2011