Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse   Donating Investigator David Ornitz,   Washington University School of Medicine

Description
Approximately 50% of mice that are homozygous for the Fgfr3^tm1Dor targeted mutation die between birth and 21 days of age. Surviving pups may live as long as 8 months. RNAase protection analysis of adult homozygous brain tissue indicates that an abnormal transcript may be generated, but that no functional protein results. Severe skeletal defects (kyphosis, scoliosis, crooked tails, curvature and overgrowth of long bones) are evident. Inner ear defects (lack of pillar cell differentiation and tunnel of Corti formation) resulting in profound deafness are also observed.

Development
A targeting vector containing neomycin resistance and two herpes simplex virus thymidine kinase genes was used to disrupt a region encoding the Ig-like domains II and III as well as the transmembrane domain. The construct was electroporated into 129S6/SvEv-derived SM-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were backcrossed to C57BL/6 mice.

Related Strains

Strains carrying other alleles of Fgfr3

014182

CByJ.Cg-Fgfr3m1J/GrsrJ

View Strains carrying other alleles of Fgfr3     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- No similarity to the expected human disease phenotype was found. One or more human genes are associated with this human disease. The mouse genotype may involve mutations to orthologs of one or more of these genes, but the phenotype did not resemble the disease.

Achondroplasia; ACH
Hypochondroplasia; HCH

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Bladder Cancer   (FGFR3) Camptodactyly, Tall Stature, and Hearing Loss Syndrome   (FGFR3) Cervical Cancer   (FGFR3) Colorectal Cancer; CRC   (FGFR3) Crouzon Syndrome with Acanthosis Nigricans; CAN   (FGFR3) Lacrimoauriculodentodigital Syndrome; LADD   (FGFR3) Muenke Syndrome; MNKES   (FGFR3) Nevus, Epidermal   (FGFR3) Testicular Germ Cell Tumor; TGCT   (FGFR3) Thanatophoric Dysplasia, Type I; TD1   (FGFR3) Thanatophoric Dysplasia, Type II; TD2   (FGFR3)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Fgfr3^tm1Dor/Fgfr3^tm1Dor

        involves: 129S6/SvEvTac * C57BL/6

• mortality/aging
• partial postnatal lethality
  • 48% die between birth and 21 days of age   (MGI Ref ID J:32991)
• premature death
  • mice die at various ages between 1 day and 8 months of age   (MGI Ref ID J:32991)
• growth/size phenotype
• decreased body weight
  • weight ranges from 17-93% of that of controls   (MGI Ref ID J:32991)
• small thoracic cavity   (MGI Ref ID J:32991)
• hearing/vestibular/ear phenotype
• abnormal cochlea morphology
  • adult cochleas resemble those of normal newborn mice   (MGI Ref ID J:32991)
  • the blood vessel below the basilar membrane is patent and numerous mesothelial cells are present below the basilar membrane   (MGI Ref ID J:32991)
• • abnormal organ of Corti morphology   (MGI Ref ID J:32991)
  • • abnormal cochlear outer hair cell morphology
      • reduced innervation of outer hair cells   (MGI Ref ID J:32991)
    • • abnormal cochlear OHC efferent innervation pattern   (MGI Ref ID J:32991)
    • abnormal pillar cell differentiation   (MGI Ref ID J:32991)
    • absent pillar cells
      • no recognizable inner and outer pillar cells between 15 days and 7 months of age   (MGI Ref ID J:32991)
    • absent tunnel of Corti   (MGI Ref ID J:32991)
    • increased Deiters cell number
      • as expected, homozygotes exhibit one row of Deiters' cells beneath each of the 3-4 rows of OHCs   (MGI Ref ID J:32991)
      • however, homozygotes also have two rows of "Deiters'-like cells", probably due to failure of these cells to develop into pillar cells   (MGI Ref ID J:32991)
• deafness   (MGI Ref ID J:32991)
• increased or absent threshold for auditory brainstem response
  • at 3 weeks to 6 months, homozygotes show no auditory brainstem responses at 100 dB SPL, indicating profound deafness   (MGI Ref ID J:32991)
• sensorineural hearing loss   (MGI Ref ID J:32991)
• skeleton phenotype
• abnormal axial skeleton morphology   (MGI Ref ID J:32991)
• • abnormal rib morphology
    • ribs are abnormally shaped, resulting in a reduction of thoracic cavity volume   (MGI Ref ID J:32991)
  • enlarged vertebral body
    • overgrowth of the lumbar vertebral bodies in 6 month old mice   (MGI Ref ID J:32991)
  • kyphosis
    • primarily in the cervical and upper thoracic spine   (MGI Ref ID J:32991)
    • first observed at 1 week after birth and develops in all mice by several months of age   (MGI Ref ID J:32991)
  • scoliosis
    • severe scoliosis, primarily in the cervical and upper thoracic spine   (MGI Ref ID J:32991)
• abnormal long bone morphology   (MGI Ref ID J:32991)
• • abnormal femur morphology   (MGI Ref ID J:32991)
  • • bowed femur
      • increased curvature of the femur in 7 week or older mice   (MGI Ref ID J:32991)
    • long femur
      • femurs at 4.5 months of age or older are 6-27% longer than controls   (MGI Ref ID J:32991)
  • abnormal humerus morphology
    • overgrowth of the humerus in 6 month or older mice   (MGI Ref ID J:32991)
  • • bowed humerus
      • 75% of 7 week or older mice exhibit increased curvature of the humerus   (MGI Ref ID J:32991)
  • abnormal long bone hypertrophic chondrocyte zone
    • growth plates contain more hypertrophic chondrocytes than controls   (MGI Ref ID J:32991)
  • • increased width of hypertrophic chondrocyte zone
      • consistent increase in the size of hypertrophic zones   (MGI Ref ID J:32991)
      • height of the proximal tibial hypertrophic zone at E18.5 and P1 is increased 33-50%   (MGI Ref ID J:32991)
  • increased long bone epiphyseal plate size
    • growth plates of long bones are longer at 3 weeks of age   (MGI Ref ID J:32991)
    • acellular bands in growth plates are narrower and less numerous than in controls   (MGI Ref ID J:32991)
• behavior/neurological phenotype
• absent gastric milk in neonates
  • several hours after birth, have smaller milk spots, indicating poor nursing   (MGI Ref ID J:32991)
• limbs/digits/tail phenotype
• abnormal femur morphology   (MGI Ref ID J:32991)
• • bowed femur
    • increased curvature of the femur in 7 week or older mice   (MGI Ref ID J:32991)
  • long femur
    • femurs at 4.5 months of age or older are 6-27% longer than controls   (MGI Ref ID J:32991)
• abnormal humerus morphology
  • overgrowth of the humerus in 6 month or older mice   (MGI Ref ID J:32991)
• • bowed humerus
    • 75% of 7 week or older mice exhibit increased curvature of the humerus   (MGI Ref ID J:32991)
• kinked tail
  • tail kinks or bends are first observed at P1 and develop in 72% of mice   (MGI Ref ID J:32991)
• nervous system phenotype
• abnormal cochlear outer hair cell morphology
  • reduced innervation of outer hair cells   (MGI Ref ID J:32991)
• • abnormal cochlear OHC efferent innervation pattern   (MGI Ref ID J:32991)
• cellular phenotype
• abnormal pillar cell differentiation   (MGI Ref ID J:32991)

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Fgfr3^tm1Dor/Fgfr3^tm1Dor

        CBA/Ca.129S6(B6)-Fgfr3^tm1Dor

• hearing/vestibular/ear phenotype
• abnormal cochlear sensory epithelium morphology
  • homozygotes exhibit an expansion of the sensory epithelium to include one extra OHC row and accompanying Dieters cells   (MGI Ref ID J:117235)
• • abnormal cochlear hair cell morphology
    • at 4 weeks, homozygotes lack a well-defined separation between IHCs and OHCs   (MGI Ref ID J:117235)
  • • increased cochlear outer hair cell number
      • no extra OHC row is noted on a mixed 129S6/SvEvTac x C57BL/6 genetic background   (MGI Ref ID J:117235)
      • on a CBA/CaJ congenic background, E17.5 homozygotes on a with an extra row of Dieters cells display an extra fourth row of OHCs in the apical two thirds of the cochlea   (MGI Ref ID J:117235)
      • an extra OHC row occurs precisely at the transition from 3 to 4 rows of Dieters cells; however, OHC stereociliary bundle formation and overall cochlear length remain normal   (MGI Ref ID J:117235)
• abnormal pillar cell differentiation
  • at P0, homozygotes display failure of pillar cell differentiation, as shown by lack of separation between inner and outer hair cells   (MGI Ref ID J:117235)
  • inner pillar cells never develop while outer pillar cell differentiation is stalled   (MGI Ref ID J:117235)
• absent pillar cells
  • homozygotes show loss of one row of pillar cells throughout the cochlea   (MGI Ref ID J:117235)
• absent tunnel of Corti
  • adult homozygotes show a complete lack of tunnel formation   (MGI Ref ID J:117235)
• increased Deiters cell number
  • homozygotes display an additional row of Dieters cells (i.e. 4 rows instead of 3) in the apical two thirds of the cochlea   (MGI Ref ID J:117235)
• increased or absent threshold for auditory brainstem response
  • homozygotes display a 50-60 dB threshold shift across all frequencies   (MGI Ref ID J:117235)
• sensorineural hearing loss
  • homozygotes display a severe hearing loss due to pillar defects   (MGI Ref ID J:117235)
• nervous system phenotype
• abnormal cochlear hair cell morphology
  • at 4 weeks, homozygotes lack a well-defined separation between IHCs and OHCs   (MGI Ref ID J:117235)
• • increased cochlear outer hair cell number
    • no extra OHC row is noted on a mixed 129S6/SvEvTac x C57BL/6 genetic background   (MGI Ref ID J:117235)
    • on a CBA/CaJ congenic background, E17.5 homozygotes on a with an extra row of Dieters cells display an extra fourth row of OHCs in the apical two thirds of the cochlea   (MGI Ref ID J:117235)
    • an extra OHC row occurs precisely at the transition from 3 to 4 rows of Dieters cells; however, OHC stereociliary bundle formation and overall cochlear length remain normal   (MGI Ref ID J:117235)
• cellular phenotype
• abnormal pillar cell differentiation
  • at P0, homozygotes display failure of pillar cell differentiation, as shown by lack of separation between inner and outer hair cells   (MGI Ref ID J:117235)
  • inner pillar cells never develop while outer pillar cell differentiation is stalled   (MGI Ref ID J:117235)

Fgfr3^tm1Dor/Fgfr3^tm1Dor

        involves: 129S6/SvEvTac

• skeleton phenotype
• abnormal axial skeleton morphology
  • the axial skeleton is elongated in neonates compared to controls   (MGI Ref ID J:109505)
• abnormal long bone epiphyseal plate morphology
  • there is also a slight but significant increase in proliferating cells of the epiphyses (16.5% versus 13.03%)   (MGI Ref ID J:109505)
• • increased width of hypertrophic chondrocyte zone
    • depth of both type II and type X collagen immunoreactive cells is increased in the cartilage of the tibial epiphysis of neonates   (MGI Ref ID J:109505)
    • there is a disproportionate increase in the depth of type X positive cells that demarcate the hypertrophic zone   (MGI Ref ID J:109505)
• long femur
  • femur length of neonates is 2.78 mm versus 2.46 mm in wild-type neonates   (MGI Ref ID J:109505)
• long humerus
  • humerus length of neonates is 3.43 mm versus 2.8 mm in wild-type neonates   (MGI Ref ID J:109505)
• long radius
  • radius length of neonates is 3.8 mm versus 3.04 mm in wild-type neonates   (MGI Ref ID J:109505)
• long ulna
  • ulna is longer in neonates than in controls   (MGI Ref ID J:109505)
• nervous system phenotype
• *normal* nervous system phenotype
  • mutants do not show defects in brain morphology and development (hindbrain patterning, boundary development or neurotransmitter system)   (MGI Ref ID J:118802)
  • mice do not display any defects in motor neuron patterning   (MGI Ref ID J:122940)
• limbs/digits/tail phenotype
• long femur
  • femur length of neonates is 2.78 mm versus 2.46 mm in wild-type neonates   (MGI Ref ID J:109505)
• long humerus
  • humerus length of neonates is 3.43 mm versus 2.8 mm in wild-type neonates   (MGI Ref ID J:109505)
• long radius
  • radius length of neonates is 3.8 mm versus 3.04 mm in wild-type neonates   (MGI Ref ID J:109505)
• long ulna
  • ulna is longer in neonates than in controls   (MGI Ref ID J:109505)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Fgfr3^tm1Dor related

Cell Biology Research
Cell Cycle Regulation
Defects in Extracellular Matrix Molecules
Genes Regulating Growth and Proliferation

Developmental Biology Research
Mesodermal Defects
Skeletal Defects

Internal/Organ Research
Wound Healing

Neurobiology Research
Hearing Defects
      deafness, neurosensory 3

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Fgfr3tm1Dor
Allele Name		targeted mutation 1, David M Ornitz
Allele Type		Targeted (knock-out)
Common Name(s)		Fgfr3 -;
Mutation Made By		David Ornitz,   Washington University School of Medicine
Strain of Origin		129S6/SvEvTac
ES Cell Line Name		SM1
ES Cell Line Strain		129S6/SvEvTac
Gene Symbol and Name		Fgfr3, fibroblast growth factor receptor 3
Chromosome		5
Gene Common Name(s)		ACH; CD333; CEK2; Fgfr-3; HBGFR; HSFGFR3EX; JTK4; sam3;
Molecular Note		A neomycin cassette replaced 3 kb of sequence that encodes the Ig-like domain II through the transmembrane domain. RNAase protection analysis on samples derived from homozygous mutant adult brain indicates that this allele produces an aberrant transcript. However, any translation product produced would be unable to bind ligand and is predicted not to be transported to the cell surface. [MGI Ref ID J:32991]

Genotyping

Genotyping Information

Genotyping Protocols

Fgfr3^tm1Dor, Standard PCR
NEOTD (Generic Neo), Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Colvin JS; Bohne BA; Harding GW; McEwen DG; Ornitz DM. 1996. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12(4):390-7. [PubMed: 8630492]  [MGI Ref ID J:32991]

Additional References

Naski MC; Colvin JS; Coffin JD; Ornitz DM. 1998. Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125(24):4977-88. [PubMed: 9811582]  [MGI Ref ID J:50292]

Fgfr3^tm1Dor related

Amizuka N; Davidson D; Liu H; Valverde-Franco G; Chai S; Maeda T; Ozawa H; Hammond V; Ornitz DM; Goltzman D; Henderson JE. 2004. Signalling by fibroblast growth factor receptor 3 and parathyroid hormone-related peptide coordinate cartilage and bone development. Bone 34(1):13-25. [PubMed: 14751559]  [MGI Ref ID J:109505]

Arnaud-Dabernat S; Kritzik M; Kayali AG; Zhang YQ; Liu G; Ungles C; Sarvetnick N. 2007. FGFR3 is a negative regulator of the expansion of pancreatic epithelial cells. Diabetes 56(1):96-106. [PubMed: 17192470]  [MGI Ref ID J:121934]

Arteaga-Solis E; Settembre C; Ballabio A; Karsenty G. 2012. Sulfatases are determinants of alveolar formation. Matrix Biol 31(4):253-60. [PubMed: 22366163]  [MGI Ref ID J:188307]

Blak AA; Naserke T; Saarimaki-Vire J; Peltopuro P; Giraldo-Velasquez M; Vogt Weisenhorn DM; Prakash N; Sendtner M; Partanen J; Wurst W. 2007. Fgfr2 and Fgfr3 are not required for patterning and maintenance of the midbrain and anterior hindbrain. Dev Biol 303(1):231-43. [PubMed: 17150206]  [MGI Ref ID J:118802]

Chung WC; Moyle SS; Tsai PS. 2008. Fibroblast growth factor 8 signaling through fibroblast growth factor receptor 1 is required for the emergence of gonadotropin-releasing hormone neurons. Endocrinology 149(10):4997-5003. [PubMed: 18566132]  [MGI Ref ID J:141766]

Davidson D; Blanc A; Filion D; Wang H; Plut P; Pfeffer G; Buschmann MD; Henderson JE. 2005. Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J Biol Chem 280(21):20509-15. [PubMed: 15781473]  [MGI Ref ID J:99916]

Hayashi T; Cunningham D; Bermingham-McDonogh O. 2007. Loss of Fgfr3 leads to excess hair cell development in the mouse organ of Corti. Dev Dyn 236(2):525-33. [PubMed: 17117437]  [MGI Ref ID J:117235]

Jungnickel J; Gransalke K; Timmer M; Grothe C. 2004. Fibroblast growth factor receptor 3 signaling regulates injury-related effects in the peripheral nervous system. Mol Cell Neurosci 25(1):21-9. [PubMed: 14962737]  [MGI Ref ID J:96765]

Jungnickel J; Klutzny A; Guhr S; Meyer K; Grothe C. 2005. Regulation of neuronal death and calcitonin gene-related peptide by fibroblast growth factor-2 and FGFR3 after peripheral nerve injury: evidence from mouse mutants. Neuroscience 134(4):1343-50. [PubMed: 16009496]  [MGI Ref ID J:104421]

Kirjavainen A; Sulg M; Heyd F; Alitalo K; Yla-Herttuala S; Moroy T; Petrova TV; Pirvola U. 2008. Prox1 interacts with Atoh1 and Gfi1, and regulates cellular differentiation in the inner ear sensory epithelia. Dev Biol 322(1):33-45. [PubMed: 18652815]  [MGI Ref ID J:141989]

Koziel L; Kunath M; Kelly OG; Vortkamp A. 2004. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell 6(6):801-13. [PubMed: 15177029]  [MGI Ref ID J:92212]

Lahti L; Saarimaki-Vire J; Rita H; Partanen J. 2011. FGF signaling gradient maintains symmetrical proliferative divisions of midbrain neuronal progenitors. Dev Biol 349(2):270-82. [PubMed: 21074523]  [MGI Ref ID J:168023]

Metcalf JA; Zhang Y; Hilton MJ; Long F; Ponder KP. 2009. Mechanism of shortened bones in mucopolysaccharidosis VII. Mol Genet Metab 97(3):202-11. [PubMed: 19375967]  [MGI Ref ID J:150606]

Naski MC; Colvin JS; Coffin JD; Ornitz DM. 1998. Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125(24):4977-88. [PubMed: 9811582]  [MGI Ref ID J:50292]

Oh LY; Denninger A; Colvin JS; Vyas A; Tole S; Ornitz DM; Bansal R. 2003. Fibroblast growth factor receptor 3 signaling regulates the onset of oligodendrocyte terminal differentiation. J Neurosci 23(3):883-94. [PubMed: 12574417]  [MGI Ref ID J:81919]

Puligilla C; Feng F; Ishikawa K; Bertuzzi S; Dabdoub A; Griffith AJ; Fritzsch B; Kelley MW. 2007. Disruption of fibroblast growth factor receptor 3 signaling results in defects in cellular differentiation, neuronal patterning, and hearing impairment. Dev Dyn 236(7):1905-17. [PubMed: 17557302]  [MGI Ref ID J:122378]

Rochester JR; Chung WC; Hayes TB; Tsai PS. 2012. Opposite-sex housing reactivates the declining GnRH system in aged transgenic male mice with FGF signaling deficiency. Am J Physiol Endocrinol Metab 303(12):E1428-39. [PubMed: 23047985]  [MGI Ref ID J:192116]

Shirasaki R; Lewcock JW; Lettieri K; Pfaff SL. 2006. FGF as a target-derived chemoattractant for developing motor axons genetically programmed by the LIM code. Neuron 50(6):841-53. [PubMed: 16772167]  [MGI Ref ID J:122940]

Timmer M; Cesnulevicius K; Winkler C; Kolb J; Lipokatic-Takacs E; Jungnickel J; Grothe C. 2007. Fibroblast growth factor (FGF)-2 and FGF receptor 3 are required for the development of the substantia nigra, and FGF-2 plays a crucial role for the rescue of dopaminergic neurons after 6-hydroxydopamine lesion. J Neurosci 27(3):459-71. [PubMed: 17234579]  [MGI Ref ID J:117417]

Valverde-Franco G; Binette JS; Li W; Wang H; Chai S; Laflamme F; Tran-Khanh N; Quenneville E; Meijers T; Poole AR; Mort JS; Buschmann MD; Henderson JE. 2006. Defects in articular cartilage metabolism and early arthritis in fibroblast growth factor receptor 3 deficient mice. Hum Mol Genet 15(11):1783-92. [PubMed: 16624844]  [MGI Ref ID J:109576]

Valverde-Franco G; Liu H; Davidson D; Chai S; Valderrama-Carvajal H; Goltzman D; Ornitz DM; Henderson JE. 2004. Defective bone mineralization and osteopenia in young adult FGFR3-/- mice. Hum Mol Genet 13(3):271-84. [PubMed: 14681299]  [MGI Ref ID J:90055]

Vidrich A; Buzan JM; Brodrick B; Ilo C; Bradley L; Fendig KS; Sturgill T; Cohn SM. 2009. Fibroblast growth factor receptor-3 regulates Paneth cell lineage allocation and accrual of epithelial stem cells during murine intestinal development. Am J Physiol Gastrointest Liver Physiol 297(1):G168-78. [PubMed: 19407216]  [MGI Ref ID J:151194]

Zhao H; Yang T; Madakashira BP; Thiels CA; Bechtle CA; Garcia CM; Zhang H; Yu K; Ornitz DM; Beebe DC; Robinson ML. 2008. Fibroblast growth factor receptor signaling is essential for lens fiber cell differentiation. Dev Biol 318(2):276-88. [PubMed: 18455718]  [MGI Ref ID J:136711]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & Husbandry	This strain originated on a B6;129S6 background and has been backcrossed to C57BL/6 for at least two generations (12/01).

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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