ORCID Profile
0000-0002-1516-1865
Current Organisation
University of Washington
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Publisher: Cold Spring Harbor Laboratory
Date: 15-06-2023
DOI: 10.1101/2023.06.15.545082
Abstract: The human embryo undergoes morphogenetic transformations following implantation into the uterus, yet our knowledge of this crucial stage is limited by the inability to observe the embryo in vivo . Stem cell-derived models of the embryo are important tools to interrogate developmental events and tissue-tissue crosstalk during these stages 1 . Here, we establish a human post-implantation embryo model comprised of embryonic and extraembryonic tissues. We combine two types of extraembryonic-like cells generated by transcription factor overexpression with wildtype embryonic stem cells and promote their self-organization into structures that mimic aspects of the post-implantation human embryo. These self-organized aggregates contain a pluripotent epiblast-like domain surrounded by hypoblast-and trophoblast-like tissues. We demonstrate that these inducible human embryoids robustly generate several cell types, including amnion, extraembryonic mesenchyme, and primordial germ cell-like cells in response to BMP signaling. This model also allowed us to identify an inhibitory role for SOX17 in the specification of anterior hypoblast-like cells 2 . Modulation of the subpopulations in the hypoblast-like compartment demonstrated that extraembryonic-like cells impact epiblast-like domain differentiation, highlighting functional tissue-tissue crosstalk. In conclusion, we present a modular, tractable, integrated 3 model of the human embryo that will allow us to probe key questions of human post-implantation development, a critical window when significant numbers of pregnancies fail.
Publisher: Springer Science and Business Media LLC
Date: 05-2022
Publisher: Elsevier BV
Date: 04-2013
Publisher: Springer Science and Business Media LLC
Date: 11-08-2013
DOI: 10.1038/NG.2727
Publisher: Elsevier BV
Date: 04-2013
Publisher: Springer Science and Business Media LLC
Date: 04-2014
DOI: 10.1038/NATURE13127
Publisher: Springer Science and Business Media LLC
Date: 27-06-2023
DOI: 10.1038/S41586-023-06368-Y
Abstract: The human embryo undergoes morphogenetic transformations following implantation into the uterus, but our knowledge of this crucial stage is limited by the inability to observe the embryo in vivo. Models of the embryo derived from stem cells are important tools for interrogating developmental events and tissue–tissue crosstalk during these stages 1 . Here we establish a model of the human post-implantation embryo, a human embryoid, comprising embryonic and extraembryonic tissues. We combine two types of extraembryonic-like cell generated by overexpression of transcription factors with wild-type embryonic stem cells and promote their self-organization into structures that mimic several aspects of the post-implantation human embryo. These self-organized aggregates contain a pluripotent epiblast-like domain surrounded by extraembryonic-like tissues. Our functional studies demonstrate that the epiblast-like domain robustly differentiates into amnion, extraembryonic mesenchyme and primordial germ cell-like cells in response to bone morphogenetic protein cues. In addition, we identify an inhibitory role for SOX17 in the specification of anterior hypoblast-like cells 2 . Modulation of the subpopulations in the hypoblast-like compartment demonstrates that extraembryonic-like cells influence epiblast-like domain differentiation, highlighting functional tissue–tissue crosstalk. In conclusion, we present a modular, tractable, integrated 3 model of the human embryo that will enable us to probe key questions of human post-implantation development, a critical window during which substantial numbers of pregnancies fail.
Publisher: Springer Science and Business Media LLC
Date: 14-09-2014
DOI: 10.1038/NG.3092
Publisher: Cold Spring Harbor Laboratory
Date: 21-02-2019
DOI: 10.1101/555797
Abstract: Multiplex Assays of Variant Effect (MAVEs), such as deep mutational scans and massively parallel reporter assays, test thousands of sequence variants in a single experiment. Despite the importance of MAVE data for basic and clinical research, there is no standard resource for their discovery and distribution. Here we present MaveDB, a public repository for large-scale measurements of sequence variant impact, designed for interoperability with applications to interpret these datasets. We also describe the first of these applications, MaveVis, which retrieves, visualizes, and contextualizes variant effect maps. Together, the database and applications will empower the community to mine these powerful datasets.
Publisher: Springer Science and Business Media LLC
Date: 04-2010
Publisher: American Association for Cancer Research (AACR)
Date: 09-2013
DOI: 10.1158/1055-9965.EPI-13-0345
Abstract: Background: Rare, inherited mutations account for 5% to 10% of all prostate cancer cases. However, to date, few causative mutations have been identified. Methods: To identify rare mutations for prostate cancer, we conducted whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early-onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 prostate cancer cases n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case–control study (n = 1,155 incident prostate cancer cases n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry. Results: The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651 P = 0.0032) and 1.2% (rs28362675 P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated prostate cancer risk in the population-based study (rs41441651: OR, 2.7 95% CI, 1.27–5.87 P = 0.010 rs28362675: OR, 2.5 95% CI, 1.16–5.46 P = 0.019). Conclusions: Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer. Impact: Results implicate BTNL2 as a novel prostate cancer susceptibility gene. Cancer Epidemiol Biomarkers Prev 22(9) 1520–8. ©2013 AACR.
Publisher: Springer Science and Business Media LLC
Date: 02-09-2012
DOI: 10.1038/NG.2396
Publisher: Springer Science and Business Media LLC
Date: 2011
Publisher: Springer Science and Business Media LLC
Date: 17-08-2023
Publisher: Springer Science and Business Media LLC
Date: 26-05-2013
DOI: 10.1038/NG.2646
No related grants have been discovered for Jay Shendure.