Редактирование: FGFR3 (раздел)

==Publications==

{{medline-entry
|title=New evidence for positive selection helps explain the paternal age effect observed in achondroplasia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23740942
|abstract=There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome average. Moreover, these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones, known as the paternal age effect (PAE). The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single-nucleotide substitution (c.1138G>A) in [[FGFR3]]. To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline, we examined the spatial distribution of the c.1138G>A substitution in a testis from an 80-year-old unaffected man. Using a technology based on bead-emulsion amplification, we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false-positive rate lower than 2.7 × 10(-6). We observed that most mutations are clustered in a few pieces with 95% of all mutations occurring in 27% of the total testis. Using computational simulations, we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site. Instead, we determined that the observed mutation distribution fits a germline selection model, where mutant spermatogonial stem cells have a proliferative advantage over unmutated cells. Combined with data on several other PAE mutations, our results support the idea that the PAE, associated with a number of Mendelian disorders, may be explained primarily by a selective mechanism. 
|mesh-terms=* Achondroplasia
* Aged, 80 and over
* Aging
* Computer Simulation
* Germ-Line Mutation
* Humans
* Male
* Models, Genetic
* Paternal Age
* Polymorphism, Single Nucleotide
* Receptor, Fibroblast Growth Factor, Type 3
* Selection, Genetic
* Spermatogonia
* Testis

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781639
}}
{{medline-entry
|title=Opposite-sex housing reactivates the declining GnRH system in aged transgenic male mice with FGF signaling deficiency.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23047985
|abstract=The continued presence of gonadotropin-releasing hormone (GnRH) neurons is required for a healthy reproductive lifespan, but factors that maintain postnatal GnRH neurons have not been identified. To begin to understand these factors, we investigated whether 1) fibroblast growth factor (FGF) signaling and 2) interactions with the opposite sex are involved in the maintenance of the postnatal GnRH system. A transgenic mouse model (dnFGFR mouse) with the targeted expression of a dominant-negative FGF receptor (dnFGFR) in GnRH neurons was used to examine the consequence of FGF signaling deficiency on postnatal GnRH neurons. Male dnFGFR mice suffered a significant loss of postnatal GnRH neurons within the first 100 days of life. Interestingly, this loss was reversed after cohabitation with female, but not male, mice for 300-550 days. Along with a rescue in GnRH neuron numbers, opposite-sex housing in dnFGFR males also increased hypothalamic GnRH peptide levels, promoted a more mature GnRH neuronal morphology, facilitated litter production, and enhanced testicular morphology. Last, mice hypomorphic for [[FGFR3]] exhibited a similar pattern of postnatal GnRH neuronal loss as dnFGFR males, suggesting FGF signaling acts, in part, through [[FGFR3]] to enhance the maintenance of the postnatal GnRH system. In summary, we have shown that FGF signaling is required for the continued presence of postnatal GnRH neurons. However, this requirement is not absolute, since sexual interactions can compensate for defects in FGFR signaling, thereby rescuing the declining GnRH system. This suggests the postnatal GnRH system is highly plastic and capable of responding to environmental stimuli throughout adult life.
|mesh-terms=* Aging
* Animals
* Cell Count
* Fibroblast Growth Factor 3
* Gonadotropin-Releasing Hormone
* Heterozygote
* Hypothalamus
* Male
* Mice
* Mice, Knockout
* Mice, Transgenic
* Nerve Degeneration
* Nerve Tissue Proteins
* Neurons
* Receptor, Fibroblast Growth Factor, Type 3
* Receptors, LHRH
* Sexual Behavior, Animal
* Signal Transduction
* Synaptic Transmission
* Testis

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532464
}}
{{medline-entry
|title=Intraventricular injection of FGF-2 promotes generation of oligodendrocyte-lineage cells in the postnatal and adult forebrain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22951928
|abstract=[[FGF2]] is considered a key factor in the generation of oligodendrocytes (OLs) derived from neural stem cells (NSCs) located within the subventricular zone (SVZ). Here, we have examined [[FGF2]] signaling in the forebrain of postnatal and adult mice. Using qPCR of microdissected microdomains of the dorsal SVZ (dSVZ) and lateral SVZ (lSVZ), and prominin1-sorted NSCs purified from these microdomains, we show that transcripts for FGF receptor 1 (FGFR1) and [[FGFR2]] are enriched in the dSVZ, from which OLs are largely derived, whereas [[FGFR3]] are significantly enriched within prominen1-sorted NSC of the lSVZ, which mainly generate olfactory interneurons. We show that direct administration of [[FGF2]] into the lateral ventricle increased the generation of oligodendrocyte progenitors (OPCs) throughout the SVZ, both within the dSVZ and ectopically in the lSVZ and ependymal wall of the SVZ. Furthermore, [[FGF2]] stimulated proliferation of neural progenitors (NPs) and their differentiation into OPCs. The results indicate that [[FGF2]] increased specification of OPCs, inducing NPs to follow an oligodendrocyte developmental pathway. Notably, [[FGF2]] did not block OPC differentiation and increased the number of oligodendrocytes in the periventricular white matter (PVWM) and cortex. However, [[FGF2]] markedly disrupted myelination in the PVWM. A key finding was that [[FGF2]] had equivalent actions on the generation of OPCs and myelin disruption in postnatal and adult mice. This study demonstrates a central role for [[FGF2]] in promoting oligodendrocyte generation in the developing and adult brain.
|mesh-terms=* Age Factors
* Aging
* Animals
* Animals, Newborn
* Cell Lineage
* Cerebral Ventricles
* Fibroblast Growth Factor 2
* Injections, Intraventricular
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Neurogenesis
* Oligodendroglia
* Prosencephalon

|full-text-url=https://sci-hub.do/10.1002/glia.22413
}}
{{medline-entry
|title=[[FGFR3]] is a negative regulator of the expansion of pancreatic epithelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17192470
|abstract=Fibroblast growth factors (FGFs) and their receptors (FGFRs) are key signaling molecules for pancreas development. Although [[FGFR3]] is a crucial developmental gene, acting as a negative regulator of bone formation, its participation remains unexplored in pancreatic organogenesis. We found that [[FGFR3]] was expressed in the epithelia in both mouse embryonic and adult regenerating pancreata but was absent in normal adult islets. In [[FGFR3]] knockout mice, we observed an increase in the proliferation of epithelial cells in neonates, leading to a marked increase in islet areas in adults. In vitro studies showed that [[FGF9]] is a very potent ligand for [[FGFR3]] and activates extracellular signal-related kinases (ERKs) in pancreatic cell lines. Moreover, [[FGFR3]] blockade or [[FGFR3]] deficiency led to increased proliferation of pancreatic epithelial cells in vivo. This was accompanied by an increase in the proportion of potential islet progenitor cells. Thus, our results show that [[FGFR3]] signaling inhibits the expansion of the immature pancreatic epithelium. Consequently, this study suggests that [[FGFR3]] participates in regulating pancreatic growth during the emergence of mature islet cells.
|mesh-terms=* Aging
* Animals
* Animals, Newborn
* Cell Line
* Epithelial Cells
* Islets of Langerhans
* Mice
* Mice, Inbred NOD
* Mice, Knockout
* Pancreas
* Receptor, Fibroblast Growth Factor, Type 3
* Regeneration
* Signal Transduction

|full-text-url=https://sci-hub.do/10.2337/db05-1073
}}
{{medline-entry
|title=Enhanced skeletal growth of sheep heterozygous for an inactivated fibroblast growth factor receptor 3.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17032787
|abstract=Normal fibroblast growth factor receptor 3 ([[FGFR3]]) acts as a negative bone growth regulator by restricting chondrocyte proliferation and endochondral bone elongation. In sheep, a heritable mutation that inactivates [[FGFR3]] produces skeletal overgrowth when homozygous, this condition is commonly referred to as spider lamb syndrome (SLS). We hypothesized that sheep heterozygous for the inactivated [[FGFR3]] mutation ([[FGFR3]](SLS/ )) would exhibit enhanced long bone growth and greater frame size; additionally, the isolated effects of increased bone growth would translate into greater BW and larger LM area relative to normal lambs at harvest. The current study investigated bone length and LM area of [[FGFR3]](SLS/ ) sheep at maturity and during growth. At maturity, [[FGFR3]](SLS/ ) ewes exhibited a larger frame size and longer bones than normal [[FGFR3]]( / ) ewes (P < 0.05). Similarly, [[FGFR3]](SLS/ ) lambs had greater frame sizes than normal [[FGFR3]]( / ) lambs, as indicated by increased metacarpal III length and height at withers (P < 0.05). The [[FGFR3]](SLS/ ) lambs took longer than the normal [[FGFR3]]( / ) lambs to reach the 60-kg common BW harvest end point (P < 0.05). The [[FGFR3]](SLS/ ) lambs showed no difference in BW, ADG, or LM area at any age compared with normal [[FGFR3]]( / ) lambs (P > 0.2). A similar LM area produced in the context of a greater frame size and skeletal length produces a greater muscle volume, thereby potentially increasing meat yield. The results of this study suggest that [[FGFR3]](SLS/ ) animals exhibit a relaxation of the normal inhibition of chondrocyte proliferation, resulting in an increase in the overall frame size. The sheep industry could utilize the naturally occurring genetic mutation in [[FGFR3]] to potentially increase meat yields with enhanced skeletal growth as an alternative to exogenous growth promotants.
|mesh-terms=* Aging
* Animals
* Body Composition
* Bone Development
* Female
* Heterozygote
* Male
* Receptor, Fibroblast Growth Factor, Type 3
* Sheep

|full-text-url=https://sci-hub.do/10.2527/jas.2006-255
}}
{{medline-entry
|title=Expression and possible function of fibroblast growth factor 9 ([[FGF9]]) and its cognate receptors [[FGFR2]] and [[FGFR3]] in postnatal and adult retina.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/15614790
|abstract=Fibroblast growth factors (FGFs) are important regulators of retinal development and survival. We examined the expression and distribution of [[FGF9]] and its preferred receptors [[FGFR2]]IIIc and [[FGFR3]]IIIc in this tissue. [[FGF9]] transcripts in whole rat retina were detected by RT-PCR but were not present in purified cultured Muller glia. Transcripts appeared as 3.2-kb and 4.0-kb bands on Northern blots, and Western blotting of whole retina revealed [[FGF9]]-immunoreactive bands at 30 and 55 kDa. [[FGF9]] mRNA demonstrated a biphasic expression profile, elevated at birth and adulthood, but relatively decreased during terminal retinal differentiation (4-14 days postnatal). Antibody labeling broadly reflected these findings: staining in vivo was observed mainly in the inner retina (and outer plexiform layer in adults) whereas [[FGF9]] was not detectable in cultured Muller glia. In adults, [[FGF9]] in situ hybridization also showed a detectable signal in inner retina. [[FGFR2]]IIIc and [[FGFR3]]IIIc were detected by RT-PCR, and Western blotting showed both FGFRs existed as multiple forms between approximately 100-200 kDa. [[FGFR2]] and [[FGFR3]] antibodies showed prominent labeling in the inner retina, especially in proliferating cultured Muller glia. Exogenous [[FGF9]] elicited a dose-dependent increase in Muller glial proliferation in vitro. These data suggest a role for [[FGF9]] in retinal differentiation and maturation, possibly representing a neuronally derived factor acting upon glial (and other) cells.
|mesh-terms=* Aging
* Animals
* Animals, Newborn
* Cell Differentiation
* Cell Proliferation
* Dose-Response Relationship, Drug
* Fibroblast Growth Factor 9
* Fibroblast Growth Factors
* Gene Expression Regulation, Developmental
* Neuroglia
* Neurons
* Protein Isoforms
* Protein-Tyrosine Kinases
* RNA, Messenger
* Rats
* Rats, Wistar
* Receptor Protein-Tyrosine Kinases
* Receptor, Fibroblast Growth Factor, Type 2
* Receptor, Fibroblast Growth Factor, Type 3
* Receptors, Fibroblast Growth Factor
* Retina

|full-text-url=https://sci-hub.do/10.1002/jnr.20363
}}
{{medline-entry
|title=Negative autoregulation of fibroblast growth factor receptor 2 expression characterizing cranial development in cases of Apert (P253R mutation) and Pfeiffer (C278F mutation) syndromes and suggesting a basis for differences in their cranial phenotypes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11596961
|abstract=Heterogeneous mutations in the fibroblast growth factor receptor 2 gene ([[FGFR2]]) cause a range of craniosynostosis syndromes. The specificity of the Apert syndrome-affected cranial phenotype reflects its narrow mutational range: 98% of cases of Apert syndrome result from an Ser252Trp or Pro253Arg mutation in the immunoglobulin-like (Ig)IIIa extracellular subdomain of [[FGFR2]]. In contrast, a broad range of mutations throughout the extracellular domain of [[FGFR2]] causes the overlapping cranial phenotypes of Pfeiffer and Crouzon syndromes and related craniofacial dysostoses. In this paper the expression of [[FGFR1]], the IgIIIa/c and IgIIIa/b isoforms of [[FGFR2]], and [[FGFR3]] is investigated in Apert syndrome (P253R mutation)- and Pfeiffer syndrome (C278F mutation)-affected fetal cranial tissue and is contrasted with healthy human control tissues. Both [[FGFR1]] and [[FGFR3]] are normally expressed in the differentiated osteoblasts of the periosteum and osteoid, in domains overlapped by that of [[FGFR2]], which widely include preosseous cranial mesenchyme. Expression of [[FGFR2]], however, is restricted to domains of advanced osseous differentiation in both Apert syndrome- and Pfeiffer syndrome-affected cranial skeletogenesis in the presence of fibroblast growth factor (FGF)2, but not in the presence of [[FGF4]] or [[FGF7]]. Whereas expression of the [[FGFR2]]-IgIIIa/b (KGFR) isoform is restricted in normal human cranial osteogenesis, there is preliminary evidence that KGFR is ectopically expressed in Pfeiffer syndrome-affected cranial osteogenesis. Contraction of the [[FGFR2]]-IgIIIa/c (BEK) expression domain in cases of Apert syndrome- and Pfeiffer syndrome-affected fetal cranial ossification suggests that the mutant activation of this receptor, by ligand-dependent or ligand-independent means, results in negative autoregulation. This phenomenon, resulting from different mechanisms in the two syndromes, offers a model by which to explain differences in their cranial phenotypes.
|mesh-terms=* Acrocephalosyndactylia
* Aging
* Embryonic and Fetal Development
* Fetus
* Homeostasis
* Humans
* Infant
* Mutation
* Osteogenesis
* Phenotype
* Receptor Protein-Tyrosine Kinases
* Receptor, Fibroblast Growth Factor, Type 1
* Receptor, Fibroblast Growth Factor, Type 2
* Receptors, Fibroblast Growth Factor
* Skull

|full-text-url=https://sci-hub.do/10.3171/jns.2001.95.4.0660
}}
{{medline-entry
|title=Markers for bone metabolism in a long-lived case of thanatophoric dysplasia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/10890204
|abstract=We report a male patient with type 1 thanatophoric dysplasia, now eight years old, having a mutation in the [[FGFR3]] gene. Radiological examination at birth revealed that the ribs and the bones of the extremities were very short and vertebral bodies were greatly reduced in height with wide intervertebral spaces. The femurs were shaped like French telephone receivers. Because of respiratory insufficiency due to the narrow thorax, the patient has been intubated and supported by continuous mechanical ventilation since the day after birth. Since 5 years of age, despite sufficient caloric intake, his body weight never increased above 4700 g, body height 49.0 cm, head circumference 46.1 cm, and chest circumference 35.8 cm. Acanthosis nigricance and huge bilateral coral-like urolithiases has been present. His mental development was severely retarded but he was able to make emotional expressions. Although developments in motor functions could not be assessed, his neurodevelopmental milestones in social relationships and language perception seemed to be at the level of a 10 to 12 month old. His bone maturation was also severely retarded. All of the assays of his serum and urinary bone formation- or resorption-related substances were within normal limits for age. Therefore, bone formation as well as bone resorption activities seemed normal and not responsible for his growth retardation.
|mesh-terms=* Biomarkers
* Bone and Bones
* Child
* Child Development
* Humans
* Longevity
* Male
* Mutation, Missense
* Protein-Tyrosine Kinases
* Radiography
* Receptor, Fibroblast Growth Factor, Type 3
* Receptors, Fibroblast Growth Factor
* Thanatophoric Dysplasia

|full-text-url=https://sci-hub.do/10.1507/endocrj.47.supplmarch_s141
}}