FGF and Mesoderm Formation
Encyclopedia
Role of FGF Signaling in Mesoderm Formation
Mesoderm
formation is a complex developmental process involving an intricate network of signaling pathways
that coordinate their activities to ensure that a selective group of cells will eventually give rise to mesodermal tissues in the adult organism. FGF
contributes to this process not only by promoting mesoderm formation, but also by inhibiting endoderm
al development.
development, the stage is set for the specification
of the three germ layer
s : endoderm
, mesoderm
and ectoderm
, which will give rise to the adult organism. The mesoderm will eventually differentiate into numerous tissues including muscles and blood
. This process requires the precise integration of a variety of signaling pathways such as the transforming growth factor type β (TGFβ), fibroblast growth factor (FGF
), bone morphogenetic protein (BMP
), and Wnt
, to achieve the induction, specification, formation and differentiation
of the mesoderm layer within a given time and space.
and Nodal
,are essential for mesodermal induction, while FGF and Wnt are in charge of its maintenance and BMP is responsible for its patterning (2, 4). It is important to note that these pathways, in turn, depend on each other. For example, in Xenopus
, disruption of FGF signaling results in the inhibition of the Nodal-dependent induction and formation of trunk and tail mesoderm (5,6), demonstrating that TGF -ß dependent mesodermal induction is itself dependent on FGF signaling (7).
and gastrula
stages, vegetal cells (the presumptive endoderm), release signals to marginal zone
cells resulting in the induction and patterning of the mesoderm (1, 8). One of these signals, FGF, achieves this through the regulation of T box transcription factors , a strategy which is shared among Xenopus, mouse and zebrafish (9). Upon FGF binding to its receptor, FGFR, the receptor pair dimerizes and is transphosphorylated, enabling it to recruit proteins that activate Ras and Raf. This is followed by the subsequent phosphorylation of MEK and MAPK. MAPK can then enter into the nucleus and activate target transcription factors (2).
transcription factors, Brachyury
(frogs) or No tail (fish) (10), VegT (frog) or Spadetail (fish), and Tbx6 (fish and frogs) (11) are important FGF targets that play a key role in mesoderm formation (12,13). In Xenopus, zebrafish and mouse, Brachyury (bra), is required for posterior
formation (9). FGF is necessary for the initial localization of Xbra to the dorsal side
of the embryo
in the marginal zone as well as for establishing and maintaining proper expression of the transcript. Disruption of FGF signaling with an FGFR inhibitor, SU5402, results in loss of Xbra expression in embryos (14,15). FGF could activate Xbra expression through Ets2, a FGF target transcription factor that binds to an FGF-responsive element of the upstream sequence (16).
that function together, FGF4
and FGF8
(17) in Xenopus and FGF8 and FGF24 in zebrafish (18), is necessary for mesoderm formation. Interestingly, both FGF signaling and Xbra expression are maintain through a feedback loop
in which upon FGF activation, Xbra expression is turned on and Xbra then directly activates eFGF, a FGF family member (19). By keeping the FGF signal active, this feedback loop contributes to the function of Fgf4 in paraxial mesoderm specification (14). Inhibition of FGFR results in a significant reduction of both Xbra and Fgf4 expression. Although it is unlikely that Fgf8 is part of the feedback loop, it contributes to mesoderm formation by activating Fgf4 (14).
In addition to promoting mesodermal formation, FGF can also prevent endodermal development. In zebrafish, FGF activity can down-regulate Casanova, a Nodal transcription factor and thereby prevent its endodermal development function (20).
. In Xenopus, VegT activates transcription of Nodal-related genes (Xnr) genes, Activin and other mesodermal transcripts, which are responsible for initiating mesodermal formation (14,21). Using dominant negative Activin receptors in Xenopus animal caps, it has been shown that FGF signaling is crucial for mesoderm formation through the activation of this and other TGFβ family members (7,22), and this process is mediated by the VegT-dependent transcription activation.
The mesodermal induction properties of VegT are dose-dependent, such that in Xenopus animal cap explants, high doses induces dorsal mesoderm, while lower doses result in ventral mesoderm (23). Most importantly, VegT plays an significant role in Xbra expression, and this is dependent on FGF signaling. In Xenopus, disruption of FGF signaling, inhibits the transcription-inducing activity of VegT and Xbra expression, even at the doses where VegT is known to robustly induce Xbra expression. This demonstrates that VegT induction of Xbra and its subsequent function in mesoderm formation is dependent on FGF signaling (14).
Mesoderm
Mesoderm
In all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and...
formation is a complex developmental process involving an intricate network of signaling pathways
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
that coordinate their activities to ensure that a selective group of cells will eventually give rise to mesodermal tissues in the adult organism. FGF
Fibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
contributes to this process not only by promoting mesoderm formation, but also by inhibiting endoderm
Endoderm
Endoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and mesoderm , with the endoderm as the intermost layer...
al development.
Introduction
During early vertebrateVertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
development, the stage is set for the specification
Regional specification
In the field of developmental biology, regional specification is the process by which different areas are identified in the development of the early embryo. The process by which the cells become specified differs between organisms.-Cell fate determination:...
of the three germ layer
Germ layer
A germ layer, occasionally referred to as a germinal epithelium, is a group of cells, formed during animal embryogenesis. Germ layers are particularly pronounced in the vertebrates; however, all animals more complex than sponges produce two or three primary tissue layers...
s : endoderm
Endoderm
Endoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and mesoderm , with the endoderm as the intermost layer...
, mesoderm
Mesoderm
In all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and...
and ectoderm
Ectoderm
The "ectoderm" is one of the three primary germ cell layers in the very early embryo. The other two layers are the mesoderm and endoderm , with the ectoderm as the most exterior layer...
, which will give rise to the adult organism. The mesoderm will eventually differentiate into numerous tissues including muscles and blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
. This process requires the precise integration of a variety of signaling pathways such as the transforming growth factor type β (TGFβ), fibroblast growth factor (FGF
Fibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
), bone morphogenetic protein (BMP
Bone morphogenetic protein
Bone morphogenetic proteins are a group of growth factors also known as cytokines and as metabologens . Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue...
), and Wnt
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
, to achieve the induction, specification, formation and differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
of the mesoderm layer within a given time and space.
Network of Signaling Pathways
Members of the TGF β superfamily, ActivinActivin and inhibin
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual cycle...
and Nodal
NODAL
Nodal is a protein that in humans is encoded by the NODAL gene. It is a member of the TGF beta superfamily. Like many other members of this superfamily, it is involved in cell differentiation...
,are essential for mesodermal induction, while FGF and Wnt are in charge of its maintenance and BMP is responsible for its patterning (2, 4). It is important to note that these pathways, in turn, depend on each other. For example, in Xenopus
Xenopus
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
, disruption of FGF signaling results in the inhibition of the Nodal-dependent induction and formation of trunk and tail mesoderm (5,6), demonstrating that TGF -ß dependent mesodermal induction is itself dependent on FGF signaling (7).
FGF Signaling
During the blastulaBlastula
The blastula is a hollow sphere of cells formed during an early stage of embryonic development in animals . The blastula is created when the zygote undergoes the cell division process known as cleavage. The blastula is preceded by the morula and is followed by the gastrula in the developmental...
and gastrula
Gastrulation
Gastrulation is a phase early in the embryonic development of most animals, during which the single-layered blastula is reorganized into a trilaminar structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm.Gastrulation takes place after cleavage...
stages, vegetal cells (the presumptive endoderm), release signals to marginal zone
Marginal zone
The marginal zone is the region at the interface between the non-lymphoid red pulp and the lymphoid white-pulp of the spleen. A marginal zone also exists in lymph nodes.-Composition and markers:It is composed of cells derived...
cells resulting in the induction and patterning of the mesoderm (1, 8). One of these signals, FGF, achieves this through the regulation of T box transcription factors , a strategy which is shared among Xenopus, mouse and zebrafish (9). Upon FGF binding to its receptor, FGFR, the receptor pair dimerizes and is transphosphorylated, enabling it to recruit proteins that activate Ras and Raf. This is followed by the subsequent phosphorylation of MEK and MAPK. MAPK can then enter into the nucleus and activate target transcription factors (2).
Regulation of T box transcription factors
In particular, three T boxT-box
T-box refers to a group of transcription factors involved in limb and heart development. In humans and some other animals, defects in the TBX5 gene expression can lead to finger-like thumbs and ventricular septal defects in which there is no separation between the left and right ventricle of the...
transcription factors, Brachyury
Brachyury
Brachyury is a protein that in humans is encoded by the T gene. Brachyury is a transcription factor within the T-box complex of genes. It has been found in all bilaterian animals that have been screened, and is also present in the cnidaria.-History:...
(frogs) or No tail (fish) (10), VegT (frog) or Spadetail (fish), and Tbx6 (fish and frogs) (11) are important FGF targets that play a key role in mesoderm formation (12,13). In Xenopus, zebrafish and mouse, Brachyury (bra), is required for posterior
Anatomical terms of location
Standard anatomical terms of location are designations employed in science that deal with the anatomy of animals to avoid ambiguities that might otherwise arise. They are not language-specific, and thus require no translation...
formation (9). FGF is necessary for the initial localization of Xbra to the dorsal side
Anatomical terms of location
Standard anatomical terms of location are designations employed in science that deal with the anatomy of animals to avoid ambiguities that might otherwise arise. They are not language-specific, and thus require no translation...
of the embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
in the marginal zone as well as for establishing and maintaining proper expression of the transcript. Disruption of FGF signaling with an FGFR inhibitor, SU5402, results in loss of Xbra expression in embryos (14,15). FGF could activate Xbra expression through Ets2, a FGF target transcription factor that binds to an FGF-responsive element of the upstream sequence (16).
Feedback Loop
Activation of FGF by two ligandsLigand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
that function together, FGF4
FGF4
Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4 gene.-Further reading:...
and FGF8
FGF8
Fibroblast growth factor 8 is a protein that in humans is encoded by the FGF8 gene.-External links:*...
(17) in Xenopus and FGF8 and FGF24 in zebrafish (18), is necessary for mesoderm formation. Interestingly, both FGF signaling and Xbra expression are maintain through a feedback loop
Feedback
Feedback describes the situation when output from an event or phenomenon in the past will influence an occurrence or occurrences of the same Feedback describes the situation when output from (or information about the result of) an event or phenomenon in the past will influence an occurrence or...
in which upon FGF activation, Xbra expression is turned on and Xbra then directly activates eFGF, a FGF family member (19). By keeping the FGF signal active, this feedback loop contributes to the function of Fgf4 in paraxial mesoderm specification (14). Inhibition of FGFR results in a significant reduction of both Xbra and Fgf4 expression. Although it is unlikely that Fgf8 is part of the feedback loop, it contributes to mesoderm formation by activating Fgf4 (14).
Other Components/Functions of FGF
Furthermore, inhibition of other components of the FGF pathway, including Ras, Raf and the transcription factor Ets2, disrupts mesodermal formation, while their over-expression induces mesodermal markers (9).In addition to promoting mesodermal formation, FGF can also prevent endodermal development. In zebrafish, FGF activity can down-regulate Casanova, a Nodal transcription factor and thereby prevent its endodermal development function (20).
Regulation of VegT
Another key player in mesoderm formation is VegT, a maternally and zygotically expressed transcription inducer localized in the vegetal hemispherePolarity in embryogenesis
In developmental biology, a blastula embryo is divided into two hemispheres: the animal pole and the vegetal pole.The animal pole consists of small cells that divide rapidly, in contrast with the vegetal pole below it. The animal pole draws its name from its liveliness relative to the...
. In Xenopus, VegT activates transcription of Nodal-related genes (Xnr) genes, Activin and other mesodermal transcripts, which are responsible for initiating mesodermal formation (14,21). Using dominant negative Activin receptors in Xenopus animal caps, it has been shown that FGF signaling is crucial for mesoderm formation through the activation of this and other TGFβ family members (7,22), and this process is mediated by the VegT-dependent transcription activation.
The mesodermal induction properties of VegT are dose-dependent, such that in Xenopus animal cap explants, high doses induces dorsal mesoderm, while lower doses result in ventral mesoderm (23). Most importantly, VegT plays an significant role in Xbra expression, and this is dependent on FGF signaling. In Xenopus, disruption of FGF signaling, inhibits the transcription-inducing activity of VegT and Xbra expression, even at the doses where VegT is known to robustly induce Xbra expression. This demonstrates that VegT induction of Xbra and its subsequent function in mesoderm formation is dependent on FGF signaling (14).