In this project we will use state-of-the-art technologies to address fundamental questions of cell lineage commitment, segregation and morphogenesis in mammals, using the mouse as a model. This proposal focuses on the gut endoderm, an embryonic tissue that gives rise to the major cell types of many internal organs, including the thyroid, thymus, lung, stomach, liver, pancreas, intestine and bladder. A rigorous understanding of normal gut endoderm morphogenesis, including knowledge of the origin, commitment, specification and differentiation of cells generating gut endoderm and its derivative tissues, should underpin logical efforts to understand disease progression and design new therapeutic strategies for these vital organ systems. The prevailing view of germ layer formation in mammalian embryos is that the gut endoderm, along with the ectoderm and mesoderm, derives solely from the pluripotent epiblast during the process of gastrulation. Moreover, while extra-embryonic tissues interact with the epiblast to establish the body axes, they contribute solely to extra-embryonic structures, such as the yolk sac and placenta. Our studies challenge this view, and inform the hypotheses being tested in the Specific Aims of this project. The broad aim of this project is to use a combination of molecular, embryological and live imaging techniques to determine the fate of the visceral endoderm a presumed extra-embryonic tissue, and investigate its role(s) in the morphogenesis of the mammalian gut endoderm.
In Specific Aim 1, we will determine if a lineage relationship exists between the visceral endoderm and the gut endoderm tissues of the fetus and adult mouse.
In Specific Aim 2, we will elucidate the mechanisms that drive gut endoderm morphogenesis.
Specific Aim 3, investigates the sequence of events leading to the organization of extra-embryonic (visceral) endoderm cells around midline signaling centers, and test the hypothesis that this arrangement is central to midline formation and/or function. Our findings are also relevant to stem cell differentiation for cell-based therapies and disease modeling because, current protocols for the in vitro differentiation of liver lung, pancreas and other endodermal cell types assume an epiblast-only origin and specifically select against the extra-embryonic endoderm that forms prior to gastrulation.

Public Health Relevance

The gut endoderm is an embryonic tissue that gives rise to the major cell types of many internal organs, including the thyroid, thymus, lung, stomach, liver, pancreas, intestine and bladder. A rigorous understanding of normal gut endoderm formation, including knowledge of the origin, commitment, specification and differentiation of cells generating gut endoderm and tissues derived from it, should underpin logical efforts to understand endoderm disease manifestation and progression and design new therapeutic strategies for these vital organ systems. The broad aim of this project is to use a combination of molecular, embryological and imaging techniques to determine origin of the gut endoderm and investigate the cell driving its formation. Beyond shedding light on the basic biology of the process in question, our findings are relevant to stem cell differentiation for cell based therapie and disease modeling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK084391-05A1
Application #
8761206
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Carrington, Jill L
Project Start
2009-09-01
Project End
2019-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$517,436
Indirect Cost
$204,402
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Morgani, Sophie; Nichols, Jennifer; Hadjantonakis, Anna-Katerina (2017) The many faces of Pluripotency: in vitro adaptations of a continuum of in vivo states. BMC Dev Biol 17:7
Freyer, Laina; Hsu, Chih-Wei; Nowotschin, Sonja et al. (2017) Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives. Cell Rep 20:2116-2130
Wang, Qiong; Zou, Yilong; Nowotschin, Sonja et al. (2017) The p53 Family Coordinates Wnt and Nodal Inputs in Mesendodermal Differentiation of Embryonic Stem Cells. Cell Stem Cell 20:70-86
Wu, Tao; Hadjantonakis, Anna-Katerina; Nowotschin, Sonja (2017) Visualizing endoderm cell populations and their dynamics in the mouse embryo with a Hex-tdTomato reporter. Biol Open 6:678-687
Huang, Xin; Balmer, Sophie; Yang, Fan et al. (2017) Zfp281 is essential for mouse epiblast maturation through transcriptional and epigenetic control of Nodal signaling. Elife 6:
Kang, Minjung; Garg, Vidur; Hadjantonakis, Anna-Katerina (2017) Lineage Establishment and Progression within the Inner Cell Mass of the Mouse Blastocyst Requires FGFR1 and FGFR2. Dev Cell 41:496-510.e5
D'Amato, Gaetano; Luxán, Guillermo; del Monte-Nieto, Gonzalo et al. (2016) Sequential Notch activation regulates ventricular chamber development. Nat Cell Biol 18:7-20
Saiz, Nestor; Kang, Minjung; Schrode, Nadine et al. (2016) Quantitative Analysis of Protein Expression to Study Lineage Specification in Mouse Preimplantation Embryos. J Vis Exp :53654
Balmer, Sophie; Nowotschin, Sonja; Hadjantonakis, Anna-Katerina (2016) Notochord morphogenesis in mice: Current understanding & open questions. Dev Dyn 245:547-57
Saiz, Néstor; Williams, Kiah M; Seshan, Venkatraman E et al. (2016) Asynchronous fate decisions by single cells collectively ensure consistent lineage composition in the mouse blastocyst. Nat Commun 7:13463

Showing the most recent 10 out of 67 publications