FGF4

Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4 gene.^[5][6]

FGF4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1IJT
Identifiers
Aliases	FGF4, HBGF-4, HST, HST-1, HSTF1, K-FGF, KFGF, fibroblast growth factor 4, HSTF-1, FGF-4
External IDs	OMIM: 164980; MGI: 95518; HomoloGene: 1522; GeneCards: FGF4; OMA:FGF4 - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q13.3 Start 69,771,022 bp[1] End 69,775,341 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7 F5|7 88.88 cM Start 144,401,104 bp[2] End 144,418,980 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle gonad olfactory bulb tibialis anterior muscle tibial nerve skin of thigh trigeminal ganglion spinal ganglia skin of hip fundus Top expressed in Apical ectodermal ridge enamel knot lumbar subsegment of spinal cord myotome primitive streak sciatic nerve inner cell mass endoderm embryo blastocyst More reference expression data BioGPS More reference expression data
Gene ontology Molecular function heparin binding fibroblast growth factor receptor binding growth factor activity protein tyrosine kinase activity phosphatidylinositol-4,5-bisphosphate 3-kinase activity 1-phosphatidylinositol-3-kinase activity Cellular component extracellular region intracellular anatomical structure Biological process cartilage condensation MAPK cascade negative regulation of apoptotic process positive regulation of ERK1 and ERK2 cascade apoptotic process involved in morphogenesis signal transduction cell-cell signaling regulation of endothelial cell chemotaxis to fibroblast growth factor multicellular organism development embryonic limb morphogenesis mesenchymal cell proliferation positive regulation of cell division regulation of gene expression positive regulation of gene expression stem cell population maintenance chondroblast differentiation cranial suture morphogenesis positive regulation of transcription by RNA polymerase II cell differentiation positive regulation of protein phosphorylation odontogenesis of dentin-containing tooth embryonic hindlimb morphogenesis fibroblast growth factor receptor signaling pathway peptidyl-tyrosine phosphorylation positive regulation of cell population proliferation phosphatidylinositol phosphate biosynthetic process phosphatidylinositol-3-phosphate biosynthetic process cellular response to leukemia inhibitory factor regulation of signaling receptor activity positive regulation of protein kinase B signaling Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2249 14175 Ensembl ENSG00000075388 ENSMUSG00000050917 UniProt P08620 P11403 RefSeq (mRNA) NM_002007 NM_010202 RefSeq (protein) NP_001998 NP_034332 Location (UCSC) Chr 11: 69.77 – 69.78 Mb Chr 7: 144.4 – 144.42 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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 activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its oncogenic transforming activity. This gene and FGF3, another oncogenic growth factor, are located closely on chromosome 11. Co-amplification of both genes was found in various kinds of human tumors. Studies on the mouse homolog suggested a function in bone morphogenesis and limb development through the sonic hedgehog (SHH) signaling pathway.^[6]

Function

During embryonic development, the 21-kD protein FGF4 acts as a signaling molecule critical for cell survival, proliferation, and patterning. It facilitates the survival and growth of the inner cell mass during the postimplantation phase by functioning as an autocrine or paracrine ligand.^[7][8] In the apical ectodermal ridge (AER), FGF4 plays a key role in initiating and sustaining limb bud outgrowth for both forelimbs and hindlimbs.^[9] It also regulates limb digit number and programmed cell death in the interdigital mesenchyme.^[10] Altered levels or regulation of FGF4 can lead to limb abnormalities such as postaxial polydactyly and cutaneous syndactyly, collectively known as polysyndactyly. In the absence of Fgf8, FGF4 is able to compensate by rescuing skeletal defects, indicating overlapping functions of FGF4 and FGF8 in limb skeleton patterning.^[10] In zebrafish, FGF4 is required for establishing the correct left-right patterning of visceral organs such as the liver, pancreas, and heart. In this context, FGF4 functions independently of FGF8, highlighting their distinct roles in visceral organ development.^[11]

Fgf signaling pathway has also been demonstrated to drive hindgut identity during gastrointestinal development, and the up regulation of the Fgf4 in pluripotent stem cell has been used to direct their differentiation for the generation of intestinal Organoids and tissues in vitro.^[12]

Clinical significance

In canines, FGF4 retrogene insertions on chromosomes 12 and 18 have important clinical implications, particularly in relation to skeletal morphology and intervertebral disc disease (IVDD). These insertions are associated with disproportionate dwarfism characterized by shortened limbs and abnormal vertebral development.^[13][14]

The FGF4 retrogene on chromosome 12 is particularly associated with chondrodystrophy, a condition marked by shortened long bones, premature degeneration of intervertebral discs, and increased susceptibility to IVDD. These dogs often develop clinical symptoms such as spinal pain, limb weakness, and in severe cases, paralysis.^[13][14]

Meanwhile, the insertion on chromosome 18 contributes to a similar short-limbed phenotype but with variable impact on disc health. Recognition of these genetic variants has practical implications for veterinary care and breeding strategies, especially in predisposed breeds like Dachshunds, Corgis, and Basset Hounds.^[13]