FGF-8
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Fibroblast growth factor 8 (FGF-8) is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''FGF8''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.


Function

The protein encoded by this gene belongs to the
fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by the macrophages. They are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in ...
(FGF) family. FGF proteins are multifunctional signaling molecules with broad
mitogenic A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The cell cycle Mitogens ac ...
and cell survival activity, playing critical roles in embryonic development, cell proliferation,
morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...
, tissue repair, and tumor progression. FGF8 signals primarily through
fibroblast growth factor receptor 1 A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibrob ...
(FGFR1) to trigger downstream pathways involved in neural and limb development.


Neural development and brain patterning

FGF8 is essential for establishing the midbrain–hindbrain boundary (mesencephalon/metencephalon), a key signaling center during brain development. This region is defined by cross-repression between
Otx2 Homeobox protein OTX2 is a protein that in humans is encoded by the ''OTX2'' gene. Function This gene encodes a member of the bicoid sub-family of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor ...
and
Gbx2 Homeobox protein GBX-2 is a protein that in humans is encoded by the ''GBX2'' gene. Summary Gastrulation Brain Homeobox 2, or commonly known as GBX2, is a type of transcription factor that aids in the arranging of the midbrain and hindbrain d ...
, which helps maintain FGF8 expression. FGF8 then induces the expression of transcription factors, forming feedback loops that guide the development of the
midbrain The midbrain or mesencephalon is the uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, mo ...
and
hindbrain The hindbrain, rhombencephalon (shaped like a rhombus) is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Met ...
. In the
forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...
, FGF8 helps define cortical areas by regulating transcription factors such as
Emx2 Homeobox protein Emx2 is a protein that in humans is encoded by the ''EMX2'' gene. Function The homeodomain transcription factor EMX2 is critical for central nervous system and urogenital development. EMX1 (MIM 600034) and EMX2 are related to ...
, Pax6, COUP-TF1, and COUP-TF2. These factors are expressed in opposing gradients and interact to establish the anterior–posterior patterning of the cerebral cortex.


Patterning of body axes and germ layers

FGF8 plays a pivotal role in early embryonic patterning, influencing the development of all three germ layers. In the
mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical ...
, FGF8 helps regulate
somite The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryogenesis, embryonic stage of somitogenesis, along the head-to-tail axis in segmentation (biology), segmented animals. ...
formation through the
Clock and wavefront model The clock and wavefront model is a model used to describe the process of somitogenesis in vertebrates. Somitogenesis is the process by which somites, blocks of mesoderm that give rise to a variety of connective tissues, are formed. The model descri ...
, promoting segmentation and the establishment of anterior–posterior identity. In the
endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gastr ...
, FGF8 acts in coordination with
retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...
(RA) to direct organ specification. Low levels of FGF8 promote the formation of anterior endodermal derivatives such as the liver and pancreas, while higher levels specify posterior structures such as the hindgut.


Limb development and morphogenesis

FGF8 is secreted by the
apical ectodermal ridge The apical ectodermal ridge (AER) is a structure that forms from the ectodermal cells at the distal end of each limb bud and acts as a major signaling center to ensure proper development of a limb. After the limb bud induces AER formation, the AE ...
(AER) at the distal end of limb buds and is essential for limb initiation, patterning, and outgrowth. Loss of FGF8 results in limb reduction or absence, with forelimbs and proximal segments being most affected. FGF8 also influences
Sonic hedgehog Sonic hedgehog protein (SHH) is a major signaling molecule of embryonic development in humans and animals, encoded by the ''SHH'' gene. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organoge ...
(Shh) signaling and is involved in tendon and digit formation.


Craniofacial development

FGF8 also contributes to craniofacial development, including the formation of the teeth, palate, mandible, and salivary glands. Altered expression can result in craniofacial abnormalities such as cleft palate, mandibular hypoplasia, or tooth agenesis. In conclusion, FGF8 expression has effects on a person’s facial appearance, brain, lungs, heart, kidneys, and limbs. If there is not enough FGF8 or too much, there can be defects in all of these systems like limb loss, cleft lip/ palate, kidney disease, and neurodevelopmental defects.


Clinical significance

This protein is known to be a factor that supports
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
. The adult expression of this gene was once thought to be restricted to
testes A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The ...
and
ovaries The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocr ...
but has been described in several organ systems. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs reveal roles in midbrain and limb development,
organogenesis Organogenesis is the phase of embryonic development that starts at the end of gastrulation and continues until birth. During organogenesis, the three germ layers formed from gastrulation (the ectoderm, endoderm, and mesoderm) form the internal org ...
, embryo
gastrulation Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals, the blastocyst, is reorganized into a two-layered or three-layered embryo known as ...
and left-right axis determination. The alternative splicing of this gene results in four transcript variants. FGF8 has been documented to play a role in oralmaxillogacial diseases and CRISPR-cas9 gene targeting on FGF8 may be key in treating these diseases. Cleft lip and/or palate (CLP) genome wide gene analysis shows a D73H missense mutation in the FGF8 gene which reduces the binding affinity of FGF8. Loss of
TBX1 T-box transcription factor TBX1 also known as T-box protein 1 and testis-specific T-box protein is a protein that in humans is encoded by the ''TBX1'' gene. Genes in the T-box family are transcription factors that play important roles in the forma ...
and Tfap2 can result in proliferation and apoptosis in the palate cells increasing the risk of CLP. Overexpression of FGF8 due to misregulation of the Gli processing gene may result in cliliopathies. Agnathia, a malformation of the mandible, is often a lethal condition that comes from the absence of
BMP4 Bone morphogenetic protein 4 is a protein that in humans is encoded by ''BMP4'' gene. BMP4 is found on chromosome 14q22-q23. BMP4 is a member of the bone morphogenetic protein family which is part of the transforming growth factor-beta superfami ...
regulators (noggin and chordin), resulting in high levels of BMP4 signaling, which in turn drastically reduces FGF8 signaling, increasing cell death during mandibular outgrowth. Lastly, the ability for FGF8 to regulate cell proliferation has caused interest in its effects on tumors or squamous cell carcinoma. CRISPR-cas9 gene targeting methods are currently being studied to determine if they are the key to solving FGF8 mutations associated with oral diseases.


Knockout models

FGF-8 knockout models have led to lethality in gastrulating state embryos in mice models. Research has demonstrated that decreased expression of FGF-8 can alter the cleft lip pathology in mice. However, due to the importance that FGF-8 has in the development and programming in multiple organ systems, full "knockout" models have led to embryonic death in multiple studies, limiting the ability to study the removal of the morphogen in adult models. While knockout experiments have occurred with this gene, a lack of/mutation in FGF8 in the early stages of embryo development is lethal. Disruption of the gene in later developmental stages has caused several issues with limb formation and development. Researchers hope to determine a way to study the signaling molecule in the future to investigate how to prevent defects including
Kallmann syndrome Kallmann syndrome (KS) is a hereditary, genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other fo ...
.


References


Further reading

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External links


GeneReviews/NCBI/NIH/UW entry on Kallmann syndrome
* * {{Growth factor receptor modulators