Understanding the molecular logic that configures interactions between the transcription factors and signaling networks that guide the development of an entire organism is arguably one of the major challenges of modern biology, and as such, it needs good experimental systems. The mammalian blastocyst is one such system. Preimplantation mammalian embryo development - from the fertilized egg to the blastocyst stage - offers a simplified and tractable model for investigating the coordination of cell fate specification and morphogenesis at single-cell resolution across a population. The blastocyst is a universal mammalian developmental stage and a paradigm of tissue self- organization. Preimplantation embryo development involves two sequential binary cell fate decisions that give rise to three cell lineages: the pluripotent epiblast (EPI) which is the founder tissue of almost all somatic cells, and two primarily extra-embryonic lineages, the trophectoderm (TE) and primitive endoderm (PrE). The three cell lineages of the blastocyst are defined by their position, developmental potential, and marker expression. Gaining insight into the mechanistic underpinnings of cell fate specification within the blastocyst, builds on our previous findings, and is the subject of this R01 grant application. The overarching goal of this project is to exploit mouse genetic and embryological methods with single-cell resolution quantitative approaches, to understand how the pluripotent epiblast (EPI) and primitive endoderm (PrE) lineages of the blastocyst form in time and space. By live imaging EPI and PrE cells as they emerge within the ICM population, we will determine the dynamic cell behaviors driving lineage divergence within the ICM in SPECIFIC AIM 1. To delineate the gene regulatory network driving these alternate fate decisions, we will investigate the roles of NANOG and GATA6, the two transcription factors positioned at the apex of the network in SPECIFIC AIM 2. FGF4 is the secreted signal driving lineage divergence within the ICM and promoting EPI maturation.
In SPECIFIC AIM 3 we will visualize cells transducing the FGF4 signal and investigate downstream components of the FGF4 signaling cascade operating in the ICM. Since cell fate specification across the ICM population is only complete concomitant with cell sorting, in SPECIFIC AIM 4 we will seek to determine whether a cell's position impacts a its fate choice. !

Public Health Relevance

/ PUBLIC HEALTH RELEVANCE The overarching goal for this project is to understand the molecular events governing the earliest stages of mammalian development. Specifically, we will use the mouse as an experimentally tractable mammalian model system to investigate how a universal stage of mammalian development ? the blastocyst - forms. An in depth mechanistic understanding of critical events taking place during mouse development will provide the essential foundation for understanding the origin of human birth defects. Moreover, decoding the mechanics of cellular communication and their role on cell fate decisions will be a guiding light in the development of methods for directing cells towards distinct identities with therapeutic potential. !

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Development - 1 Study Section (DEV1)
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Ravindranath, Neelakanta
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Simon, Claire S; Hadjantonakis, Anna-Katerina; Schröter, Christian (2018) Making lineage decisions with biological noise: Lessons from the early mouse embryo. Wiley Interdiscip Rev Dev Biol 7:e319
Morgani, Sophie M; Saiz, Nestor; Garg, Vidur et al. (2018) A Sprouty4 reporter to monitor FGF/ERK signaling activity in ESCs and mice. Dev Biol 441:104-126