scholarly journals HIPPO signaling resolves embryonic cell fate conflicts during establishment of pluripotency in vivo

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Tristan Frum ◽  
Tayler M Murphy ◽  
Amy Ralston
Keyword(s):  
Cell Fate ◽  
Early Embryo ◽  
Embryonic Cell ◽  
Hippo Signaling ◽  
Mammalian Development ◽  
Sox2 Expression ◽  
Mouse Early Embryo ◽  
Cell Positioning ◽  
Complex Components

During mammalian development, the challenge for the embryo is to override intrinsic cellular plasticity to drive cells to distinct fates. Here, we unveil novel roles for the HIPPO signaling pathway in controlling cell positioning and expression of Sox2, the first marker of pluripotency in the mouse early embryo. We show that maternal and zygotic YAP1 and WWTR1 repress Sox2 while promoting expression of the trophectoderm gene Cdx2 in parallel. Yet, Sox2 is more sensitive than Cdx2 to Yap1/Wwtr1 dosage, leading cells to a state of conflicted cell fate when YAP1/WWTR1 activity is moderate. Remarkably, HIPPO signaling activity resolves conflicted cell fate by repositioning cells to the interior of the embryo, independent of its role in regulating Sox2 expression. Rather, HIPPO antagonizes apical localization of Par complex components PARD6B and aPKC. Thus, negative feedback between HIPPO and Par complex components ensure robust lineage segregation.

scholarly journals HIPPO signaling resolves embryonic cell fate conflicts during establishment of pluripotency in vivo

2018 ◽  
Author(s):  
Tristan Frum ◽  
Tayler Murphy ◽  
Amy Ralston
Keyword(s):  
Cell Fate ◽  
Early Embryo ◽  
Embryonic Cell ◽  
Hippo Signaling ◽  
Mammalian Development ◽  
Mouse Early Embryo ◽  
Cell Positioning ◽  
Apical Localization ◽  
Complex Components

AbstractDuring mammalian development, the challenge for the embryo is to override intrinsic cellular plasticity to drive cells to distinct fates. Here, we unveil novel roles for the HIPPO signaling pathway segregates pluripotent and extraembryonic fates by controlling cell positioning as well as expression of Sox2, the first marker of pluripotency in the mouse early embryo. We show that maternal and zygotic YAP1 and WWTR1 repress Sox2 while promoting expression of the trophectoderm gene Cdx2 in parallel. Yet, Sox2 is more sensitive than Cdx2 to Yap1/Wwtr1 dosage, leading cells to a state of conflicted cell fate when YAP1/WWTR1 activity is moderate. Remarkably, HIPPO signaling activity resolves conflicted cell fate by repositioning cells to the interior of the embryo, independent of its role in regulating Sox2 expression. Rather, HIPPO antagonizes apical localization of Par complex components PARD6B and aPKC. Thus, negative feedback between HIPPO and Par complex components ensure robust lineage segregation.

scholarly journals Prediction and control of symmetry breaking in embryoid bodies by environment and signal integration

2018 ◽  
Author(s):  
Naor Sagy ◽  
Shaked Slovin ◽  
Maya Allalouf ◽  
Maayan Pour ◽  
Gaya Savyon ◽  
...  
Keyword(s):  
Symmetry Breaking ◽  
Cell Fate ◽  
Developmental Process ◽  
Primitive Streak ◽  
Early Embryo ◽  
Embryoid Bodies ◽  
Neighboring Cell ◽  
Contact Points

AbstractDuring early embryogenesis, mechanical signals, localized biochemical signals and neighboring cell layers interaction coordinate around anteroposterior axis determination and symmetry breaking. Deciphering their relative roles, which are hard to tease apart in vivo, will enhance our understanding of how these processes are driven. In recent years, in vitro 3D models of early mammalian development, such as embryoid bodies (EBs) and gastruloids, were successful in mimicking various aspects of the early embryo, providing high throughput accessible systems for studying the basic rules shaping cell fate and morphology during embryogenesis. Using Brachyury (Bry), a primitive streak and mesendoderm marker in EBs, we study how contact, biochemical and neighboring cell cues affect the positioning of a primitive streak-like locus, determining the AP axis. We show that a Bry-competent layer must be formed in the EB before Bry expression initiates, and that Bry onset locus selection depends on contact points of the EB with its surrounding. We can maneuver Bry onset to occur at a specific locus, a few loci, or in an isotropic peripheral pattern. By spatially separating contact and biochemical signal sources, we show these two modalities can be integrated by the EB to generate a single Bry locus. Finally, we show Foxa2+ cells are predictive of the future location of Bry onset, demonstrating an earlier symmetry-breaking event. By delineating the temporal signaling pathway dependencies of Bry and Foxa2, we were able to selectively abolish either, or spatially decouple the two cell types during EB differentiation. These findings demonstrate multiple inputs integration during an early developmental process, and may prove valuable in directing in vitro differentiation.

Slow muscle induction by Hedgehog signalling in vitro

2000 ◽  
Vol 113 (15) ◽  
pp. 2695-2703 ◽  
Author(s):  
W. Norris ◽  
C. Neyt ◽  
P.W. Ingham ◽  
P.D. Currie
Keyword(s):  
Cell Fate ◽  
Sonic Hedgehog ◽  
Culture System ◽  
Early Embryo ◽  
Extrinsic Factors ◽  
Fast Myosin ◽  
Neural Input ◽  
Slow Twitch

Muscles are composed of several fibre types, the precise combination of which determines muscle function. Whereas neonatal and adult fibre type is influenced by a number of extrinsic factors, such as neural input and muscle load, there is little knowledge of how muscle cells are initially determined in the early embryo. In the zebrafish, fibres of the slow twitch class arise from precociously specified myoblasts that lie close to the midline whereas the remainder of the myotome differentiates as fast myosin expressing muscle. In vivo evidence has suggested the Sonic Hedgehog glycoprotein, secreted from the notochord, controls the formation of slow twitch and fast twitch muscle fates. Here we describe an in vitro culture system that we have developed to test directly the ability of zebrafish myoblasts to respond to exogenous Sonic Hedgehog peptide. We find that Sonic Hedgehog peptide can control the binary cell fate choice of embryonic zebrafish myoblasts in vitro. We have also used this culture system to assay the relative activities of different Hedgehog-family proteins and to investigate the possible involvement of heterotrimeric G-proteins in Hedgehog signal transduction.

In vivo analysis using variants of zebrafish BMPR-IA: range of action and involvement of BMP in ectoderm patterning

Development ◽  
1999 ◽  
Vol 126 (1) ◽  
pp. 181-190 ◽  
Author(s):  
M. Nikaido ◽  
M. Tada ◽  
H. Takeda ◽  
A. Kuroiwa ◽  
N. Ueno
Keyword(s):  
Cell Fate ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Active Form ◽  
Ectopic Expression ◽  
Signal Propagation ◽  
Early Embryo ◽  
Type I ◽  
Cell Fate Conversion

It has been an intriguing problem whether the polypeptide growth factors belonging to the transforming growth factor-beta (TGF-beta) superfamily function as direct and long-range signaling molecules in pattern formation of the early embryo. In this study, we examined the mechanism of signal propagation of bone morphogenetic protein (BMP) in the ectodermal patterning of zebrafish embryos, in which BMP functions as an epidermal inducer and a neural inhibitor. To estimate the effective range of zbmp-2, we first performed whole-mount in situ hybridization analysis. The zbmp-2-expressing domain and the neuroectoderm, marked by otx-2 expression, were complementary, suggesting that BMP has a short-range effect in vivo. Moreover, mosaic experiments using a constitutively active form of a zebrafish BMP type I receptor (CA-BRIA) demonstrated that the cell-fate conversion, revealed by ectopic expression of gata-3 and repression of otx-2, occurred in a cell-autonomous manner, denying the involvement of the relay mechanism. We also found that zbmp-2 was induced cell autonomously within the transplanted cells in the host ectoderm, suggesting that BMP cannot influence even the neighboring cells. This result is consistent with the observation that there is no gap between the expression domains of zbmp-2 and otx-2. Taken together, we propose that, in ectodermal patterning, BMP exerts a direct and cell-autonomous effect to fate uncommitted ectodermal cells to become epidermis.

scholarly journals Abnormalities of the Genitourinary Tract in Female Mice Lacking GATA5

2000 ◽  
Vol 20 (14) ◽  
pp. 5256-5260 ◽  
Author(s):  
Jeffery D. Molkentin ◽  
Kevin M. Tymitz ◽  
James A. Richardson ◽  
Eric N. Olson
Keyword(s):  
Cell Fate ◽  
Null Allele ◽  
Cell Fate Specification ◽  
Mammalian Development ◽  
Gata Factor ◽  
Genitourinary System ◽  
Gata Factors ◽  
Developing Heart

ABSTRACT Members of the GATA family of transcription factors play important roles in cell fate specification, differentiation, and morphogenesis during mammalian development. GATA5, the only one of the six vertebrate GATA factor genes not yet inactivated in mice, is expressed in a pattern that overlaps with but is distinct from that of other GATA factor genes. During mouse embryogenesis, GATA5 is expressed first in the developing heart and subsequently in the lung, vasculature, and genitourinary system. To investigate the function of GATA5 in vivo, we created mice homozygous for a GATA5 null allele. Homozygous mutants were viable and fertile, but females exhibited pronounced genitourinary abnormalities that included vaginal and uterine defects and hypospadias. In contrast, the genitourinary system was unaffected in male GATA5 mutants. These results reveal a specific role of GATA5 in development of the female genitourinary system and suggest that other GATA factors may have functions overlapping those of GATA5 in other tissues.

scholarly journals Excess histone H3 is a Chk1 inhibitor that controls embryonic cell cycle progression

2020 ◽  
Author(s):  
Yuki Shindo ◽  
Amanda A. Amodeo
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Histone H3 ◽  
Embryonic Cell ◽  
Cycle Progression ◽  
Cell Cycles ◽  
Embryonic Cell Cycle

AbstractThe early embryos of many species undergo a switch from rapid, reductive cleavage divisions to slower, cell fate-specific division patterns at the Mid-Blastula Transition (MBT). The maternally loaded histone pool is used to measure the increasing ratio of nuclei to cytoplasm (N/C ratio) to control MBT onset, but the molecular mechanism of how histones regulate the cell cycle has remained elusive. Here, we show that excess histone H3 inhibits the DNA damage checkpoint kinase Chk1 to promote cell cycle progression in the Drosophila embryo. We find that excess H3-tail that cannot be incorporated into chromatin is sufficient to shorten the embryonic cell cycle and reduce the activity of Chk1 in vitro and in vivo. Removal of the Chk1 phosphosite in H3 abolishes its ability to regulate the cell cycle. Mathematical modeling quantitatively supports a mechanism where changes in H3 nuclear concentrations over the final cell cycles leading up to the MBT regulate Chk1-dependent cell cycle slowing. We provide a novel mechanism for Chk1 regulation by H3, which is crucial for proper cell cycle remodeling during early embryogenesis.

scholarly journals Developmental plasticity, cell fate specification and morphogenesis in the early mouse embryo

2014 ◽  
Vol 369 (1657) ◽  
pp. 20130538 ◽  
Author(s):  
Ivan Bedzhov ◽  
Sarah J. L. Graham ◽  
Chuen Yan Leung ◽  
Magdalena Zernicka-Goetz
Keyword(s):  
Cell Fate ◽  
Mouse Embryo ◽  
Developmental Plasticity ◽  
Molecular Mechanisms ◽  
Imaging Techniques ◽  
Cell Signalling ◽  
Three Dimensional ◽  
Early Embryo ◽  
Mammalian Development ◽  
Cell Fate Decisions

A critical point in mammalian development is when the early embryo implants into its mother's uterus. This event has historically been difficult to study due to the fact that it occurs within the maternal tissue and therefore is hidden from view. In this review, we discuss how the mouse embryo is prepared for implantation and the molecular mechanisms involved in directing and coordinating this crucial event. Prior to implantation, the cells of the embryo are specified as precursors of future embryonic and extra-embryonic lineages. These preimplantation cell fate decisions rely on a combination of factors including cell polarity, position and cell–cell signalling and are influenced by the heterogeneity between early embryo cells. At the point of implantation, signalling events between the embryo and mother, and between the embryonic and extraembryonic compartments of the embryo itself, orchestrate a total reorganization of the embryo, coupled with a burst of cell proliferation. New developments in embryo culture and imaging techniques have recently revealed the growth and morphogenesis of the embryo at the time of implantation, leading to a new model for the blastocyst to egg cylinder transition. In this model, pluripotent cells that will give rise to the fetus self-organize into a polarized three-dimensional rosette-like structure that initiates egg cylinder formation.

Embryos, DOHaD and David Barker

2015 ◽  
Vol 6 (5) ◽  
pp. 377-383 ◽  
Author(s):  
T. P. Fleming ◽  
M. A. Velazquez ◽  
J. J. Eckert
Keyword(s):  
Short Review ◽  
Early Embryo ◽  
Embryonic Cell ◽  
Large Animal ◽  
Permanent Change ◽  
Large Animal Models ◽  
Low Protein ◽  
Periconceptional Period

The early embryo and periconceptional period is a window during which environmental factors may cause permanent change in the pattern and characteristics of development leading to risk of adult onset disease. This has now been demonstrated across small and large animal models and also in the human. Most evidence of periconceptional ‘programming’ has emerged from maternal nutritional models but also other in vivo and in vitro conditions including assisted reproductive treatments, show consistent outcomes. This short review first reports on the range of environmental in vivo and in vitro periconceptional models and resulting long-term outcomes. Second, it uses the rodent maternal low protein diet model restricted to the preimplantation period and considers the stepwise maternal-embryonic dialogue that comprises the induction of programming. This dialogue leads to cellular and epigenetic responses by the embryo, mainly identified in the extra-embryonic cell lineages, and underpins an apparently permanent change in the growth trajectory during pregnancy and associates with increased cardiometabolic and behavioural disease in adulthood. We recognize the important advice of David Barker some years ago to investigate the sensitivity of the early embryo to developmental programming, an insight for which we are grateful.

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