Glia-activating factor is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''FGF9''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Function
The protein encoded by this gene is a member of the
fibroblast growth factor
Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their ...
(FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including
embryonic development
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
, cell growth,
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 devel ...
, tissue repair, tumor growth and invasion. This protein was isolated as a secreted factor that exhibits a growth-stimulating effect on cultured
glial cell
Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...
s. In nervous system, this protein is produced mainly by neurons and may be important for glial cell development. Expression of the mouse homolog of this gene was found to be dependent on
Sonic hedgehog (Shh) signaling. Mice lacking the homolog gene displayed a male-to-female sex reversal phenotype, which suggested a role in testicular embryogenesis.
This gene is involved in the patterning of sex determination, lung development, and skeletal development.
Sex determination
FGF9 has also been shown to play a vital role in male sex development. FGF9’s role in sex determination begins with its expression in the bi-potent gonads for both females and males.
Once activated by
SOX9
Transcription factor SOX-9 is a protein that in humans is encoded by the ''SOX9'' gene.
Function
SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It is expressed by proliferating but no ...
, it is responsible for forming a feedforward loop with Sox9, increasing the levels of both genes. It forms a
positive feedback loop
Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in the ...
upregulating SOX9, while simultaneously inactivating the female
Wnt4
WNT4 is a secreted protein that in humans is encoded by the ''Wnt4'' gene, found on chromosome 1. It promotes female sex development and represses male sex development. Loss of function can have serious consequences, such as female to male sex rev ...
signaling pathway.
[ ]
Lung development
In lung development, FGF9 is expressed in the mesothelium and pulmonary epithelium, where its purpose is to retain lung mesenchymal
Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...
proliferation. Inactivation of FGF9 results in diminished epithelial branching. By the end of gestation, the lungs that are developed cannot sustain life and will result in a prenatal death.[
]
Skeletal development
Another biological role presented by this gene is its involvement in skeletal development and repair. FGF9 and FGF18
Fibroblast growth factor 18 is a protein that in humans is encoded by the ''FGF18'' gene.
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival acti ...
both stimulate chondrocyte proliferation. FGF9 heterozygous mutant mice had a compromised bone repair after an injury with less expression of VEGF
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
and VEGFR2
Kinase insert domain receptor (KDR, a type IV receptor tyrosine kinase) also known as vascular endothelial growth factor receptor 2 (VEGFR-2) is a VEGF receptor. ''KDR'' is the human gene encoding it. KDR has also been designated as CD309 (cluster ...
and lower osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...
recruitment.[ One disease associated with this gene is ]multiple synostoses syndrome
Multiple may refer to:
Economics
*Multiple finance, a method used to analyze stock prices
*Multiples of the price-to-earnings ratio
*Chain stores, are also referred to as 'Multiples'
* Box office multiple, the ratio of a film's total gross to th ...
(SYNS), a rare bone disease that has to do with the fusion of the fingers and toes. A missense mutation in the second exon of the FGF9 gene, the S99N mutation, seems to be the third cause of SYNS. A mutation in Noggin
Noggin may refer to:
General
* Noggin or gill (volume), a unit of volume
* Noggin (cup), a small cup
* Noggin, slang for head
A head is the part of an organism which usually includes the ears, brain, forehead, cheeks, chin, eyes, nose, an ...
(NOG) and the Growth Differentiation Factor 5 (GDF5
Growth/differentiation factor 5 is a protein that in humans is encoded by the ''GDF5'' gene.
The protein encoded by this gene is closely related to the bone morphogenetic protein (BMP) family and is a member of the TGF-beta superfamily. This grou ...
) are the other two causes of SYNS.[ The S99N mutation results in cell signaling irregularities that interfere with chondrogenesis and ]osteogenesis
Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts funct ...
causing the fusion of the joints during development.[
]
Overexpression of FGF9
FGF9 is a gene within the larger family of fibroblast growth factors (FGF), a type of cell signaling protein. This gene signals embryonic stem cell development and sex determination. FGF9 gene expression is also essential for development of the prostate and maintaining prostate tissue homeostasis. The prostate is a male reproductive organ that is composed of epithelial and stromal cells. Overexpression of FGF9 in prostate epithelial cells can lead to high grade prostate intraepithelial neoplasia, which is a precursor for prostate cancer. Additionally, high expression of the gene in prostate epithelial cells disrupts prostate tissue homeostasis, and promotes a high frequency of metastasis. On the other hand, overexpression of FGF9 in the alternate, prostate stromal cells, promotes the communication with prostate cancer cells.
It has been reported that abnormal expression of FGF9 has oncogenic effects in various human cancers including; ovarian, brain, lung, and colon cancers. In studies with mice, high expression of FGF9 resulted in fusion of the prostate and seminal vesicles, and penis protrusion. More importantly, it caused hyperplasia in both stromal and epithelial compartments. Due to the enlargement of tissue caused by an increase in the reproduction rate of its cells, hyperplasia is frequently the primary stage in the development of cancer.
Although several studies have proven that high expression of FGF9 correlates to the progression of prostate cancer, the question of whether overexpression of FGF9 initiates prostate tumorigenesis is still being tested.
Interactions
FGF9 has been shown to interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with Fibroblast growth factor receptor 3
Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the ''FGFR3'' gene. FGFR3 has also been designated as CD333 (cluster of differentiation 333). The gene, which is located on chromosome 4, location q16.3, is expressed in ...
.
References
Further reading
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{{Growth factor receptor modulators