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
Viotti, Manuel; Nowotschin, Sonja; Hadjantonakis, Anna-Katerina (2014) SOX17 links gut endoderm morphogenesis and germ layer segregation. Nat Cell Biol 16:1146-56
Pulina, Maria V; Sahr, Kenneth E; Nowotschin, Sonja et al. (2014) A conditional mutant allele for analysis of Mixl1 function in the mouse. Genesis 52:417-23
Ohnishi, Yusuke; Huber, Wolfgang; Tsumura, Akiko et al. (2014) Cell-to-cell expression variability followed by signal reinforcement progressively segregates early mouse lineages. Nat Cell Biol 16:27-37
Udan, Ryan S; Piazza, Victor G; Hsu, Chih-Wei et al. (2014) Quantitative imaging of cell dynamics in mouse embryos using light-sheet microscopy. Development 141:4406-14
Schrode, Nadine; Saiz, Néstor; Di Talia, Stefano et al. (2014) GATA6 levels modulate primitive endoderm cell fate choice and timing in the mouse blastocyst. Dev Cell 29:454-67
Kropp, Erin M; Bhattacharya, Subarna; Waas, Matthew et al. (2014) N-glycoprotein surfaceomes of four developmentally distinct mouse cell types. Proteomics Clin Appl 8:603-9
Lou, Xinghua; Kang, Minjung; Xenopoulos, Panagiotis et al. (2014) A rapid and efficient 2D/3D nuclear segmentation method for analysis of early mouse embryo and stem cell image data. Stem Cell Reports 2:382-97
Rayon, Teresa; Menchero, Sergio; Nieto, Andres et al. (2014) Notch and hippo converge on Cdx2 to specify the trophectoderm lineage in the mouse blastocyst. Dev Cell 30:410-22
Saijoh, Yukio; Viotti, Manuel; Hadjantonakis, Anna-Katerina (2014) Follow your gut: relaying information from the site of left-right symmetry breaking in the mouse. Genesis 52:503-14
Le Bin, Gloryn Chia; Muñoz-Descalzo, Silvia; Kurowski, Agata et al. (2014) Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst. Development 141:1001-10

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