hm1

Fgfr3^tm1Dor/Fgfr3^tm1Dor
CBA/Ca.129S6(B6)-Fgfr3^tm1Dor

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

hearing/vestibular/ear

abnormal pillar cell differentiation ( J:117235 )

• at P0, homozygotes display failure of pillar cell differentiation, as shown by lack of separation between inner and outer hair cells

• inner pillar cells never develop while outer pillar cell differentiation is stalled

abnormal cochlear sensory epithelium morphology ( J:117235 )

• homozygotes exhibit an expansion of the sensory epithelium to include one extra OHC row and accompanying Dieters cells

abnormal cochlear hair cell morphology ( J:117235 )

• at 4 weeks, homozygotes lack a well-defined separation between IHCs and OHCs

increased cochlear outer hair cell number ( J:117235 )

• Background Sensitivity: no extra OHC row is noted on a mixed 129S6/SvEvTac x C57BL/6 genetic background

• 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

• 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

increased Deiters cell number ( J:117235 )

• homozygotes display an additional row of Dieters cells (i.e. 4 rows instead of 3) in the apical two thirds of the cochlea

absent pillar cells ( J:117235 )

• homozygotes show loss of one row of pillar cells throughout the cochlea

absent tunnel of Corti ( J:117235 )

• adult homozygotes show a complete lack of tunnel formation

increased or absent threshold for auditory brainstem response ( J:117235 )

• homozygotes display a 50-60 dB threshold shift across all frequencies

sensorineural hearing loss ( J:117235 )

• homozygotes display a severe hearing loss due to pillar defects

nervous system

abnormal cochlear hair cell morphology ( J:117235 )

• at 4 weeks, homozygotes lack a well-defined separation between IHCs and OHCs

increased cochlear outer hair cell number ( J:117235 )

• Background Sensitivity: no extra OHC row is noted on a mixed 129S6/SvEvTac x C57BL/6 genetic background

• 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

• 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

cellular

abnormal pillar cell differentiation ( J:117235 )

• at P0, homozygotes display failure of pillar cell differentiation, as shown by lack of separation between inner and outer hair cells

• inner pillar cells never develop while outer pillar cell differentiation is stalled

hm2

Fgfr3^tm1Dor/Fgfr3^tm1Dor
involves: 129S6/SvEvTac

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

skeleton

long humerus ( J:109505 )

• humerus length of neonates is 3.43 mm versus 2.8 mm in wild-type neonates

long radius ( J:109505 )

• radius length of neonates is 3.8 mm versus 3.04 mm in wild-type neonates

long ulna ( J:109505 )

• ulna is longer in neonates than in controls

long femur ( J:109505 )

• femur length of neonates is 2.78 mm versus 2.46 mm in wild-type neonates

abnormal long bone epiphyseal plate morphology ( J:109505 )

• there is also a slight but significant increase in proliferating cells of the epiphyses (16.5% versus 13.03%)

increased width of hypertrophic chondrocyte zone ( J:109505 )

• depth of both type II and type X collagen immunoreactive cells is increased in the cartilage of the tibial epiphysis of neonates

• there is a disproportionate increase in the depth of type X positive cells that demarcate the hypertrophic zone

abnormal axial skeleton morphology ( J:109505 )

• the axial skeleton is elongated in neonates compared to controls

nervous system

nervous system phenotype ( J:118802 , J:122940 )

N	• mutants do not show defects in brain morphology and development (hindbrain patterning, boundary development or neurotransmitter system) (J:118802) • mice do not display any defects in motor neuron patterning (J:122940)

limbs/digits/tail

long humerus ( J:109505 )

• humerus length of neonates is 3.43 mm versus 2.8 mm in wild-type neonates

long radius ( J:109505 )

• radius length of neonates is 3.8 mm versus 3.04 mm in wild-type neonates

long ulna ( J:109505 )

• ulna is longer in neonates than in controls

long femur ( J:109505 )

• femur length of neonates is 2.78 mm versus 2.46 mm in wild-type neonates

mortality/aging

partial postnatal lethality ( J:32991 )

• 48% die between birth and 21 days of age

premature death ( J:32991 )

• mice die at various ages between 1 day and 8 months of age

growth/size

small thoracic cavity ( J:32991 )

decreased body weight ( J:32991 )

• weight ranges from 17-93% of that of controls

hearing/vestibular/ear

abnormal cochlea morphology ( J:32991 )

• adult cochleas resemble those of normal newborn mice

• the blood vessel below the basilar membrane is patent and numerous mesothelial cells are present below the basilar membrane

abnormal organ of Corti morphology ( J:32991 )

abnormal pillar cell differentiation ( J:32991 )

abnormal cochlear outer hair cell morphology ( J:32991 )

• reduced innervation of outer hair cells

abnormal cochlear OHC efferent innervation pattern ( J:32991 )

increased Deiters cell number ( J:32991 )

• as expected, homozygotes exhibit one row of Deiters' cells beneath each of the 3-4 rows of OHCs

• however, homozygotes also have two rows of "Deiters'-like cells", probably due to failure of these cells to develop into pillar cells

absent pillar cells ( J:32991 )

• no recognizable inner and outer pillar cells between 15 days and 7 months of age

absent tunnel of Corti ( J:32991 )

increased or absent threshold for auditory brainstem response ( J:32991 )

• at 3 weeks to 6 months, homozygotes show no auditory brainstem responses at 100 dB SPL, indicating profound deafness

deafness ( J:32991 )

sensorineural hearing loss ( J:32991 )

skeleton

abnormal long bone morphology ( J:32991 )

abnormal humerus morphology ( J:32991 )

• overgrowth of the humerus in 6 month or older mice

bowed humerus ( J:32991 )

• 75% of 7 week or older mice exhibit increased curvature of the humerus

abnormal femur morphology ( J:32991 )

bowed femur ( J:32991 )

• increased curvature of the femur in 7 week or older mice

long femur ( J:32991 )

• femurs at 4.5 months of age or older are 6-27% longer than controls

abnormal long bone hypertrophic chondrocyte zone ( J:32991 )

• growth plates contain more hypertrophic chondrocytes than controls

increased width of hypertrophic chondrocyte zone ( J:32991 )

• consistent increase in the size of hypertrophic zones

• height of the proximal tibial hypertrophic zone at E18.5 and P1 is increased 33-50%

increased long bone epiphyseal plate size ( J:32991 )

• growth plates of long bones are longer at 3 weeks of age

• acellular bands in growth plates are narrower and less numerous than in controls

abnormal axial skeleton morphology ( J:32991 )

abnormal rib morphology ( J:32991 )

• ribs are abnormally shaped, resulting in a reduction of thoracic cavity volume

kyphosis ( J:32991 )

• primarily in the cervical and upper thoracic spine

• first observed at 1 week after birth and develops in all mice by several months of age

scoliosis ( J:32991 )

• severe scoliosis, primarily in the cervical and upper thoracic spine

enlarged vertebral body ( J:32991 )

• overgrowth of the lumbar vertebral bodies in 6 month old mice

behavior/neurological

absent gastric milk in neonates ( J:32991 )

• several hours after birth, have smaller milk spots, indicating poor nursing

limbs/digits/tail

abnormal humerus morphology ( J:32991 )

• overgrowth of the humerus in 6 month or older mice

bowed humerus ( J:32991 )

• 75% of 7 week or older mice exhibit increased curvature of the humerus

abnormal femur morphology ( J:32991 )

bowed femur ( J:32991 )

• increased curvature of the femur in 7 week or older mice

long femur ( J:32991 )

• femurs at 4.5 months of age or older are 6-27% longer than controls

kinked tail ( J:32991 )

• tail kinks or bends are first observed at P1 and develop in 72% of mice

nervous system

abnormal cochlear outer hair cell morphology ( J:32991 )

• reduced innervation of outer hair cells

abnormal cochlear OHC efferent innervation pattern ( J:32991 )

cellular

abnormal pillar cell differentiation ( J:32991 )

Mouse Models of Human Disease		OMIM ID	Ref(s)
NOT	Achondroplasia; ACH	100800	J:32991
NOT	Hypochondroplasia; HCH	146000	J:32991

cx4

Fgfr3^tm1Dor/Fgfr3^tm1Dor
Pthlh^tm1Fbe/Pthlh^tm1Fbe
involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

mortality/aging

complete neonatal lethality ( J:109505 )

• neonatal lethality occurs to these mice

skeleton

short humerus ( J:109505 )

• humerus length of neonates is 2.10 mm versus 2.80 mm in wild-type neonates

short radius ( J:109505 )

• radius length of neonates is 2.30 mm versus 3.04 mm in wild-type neonates

short ulna ( J:109505 )

• is observed in neonates compared to controls

short femur ( J:109505 )

• femur length of neonates is 2.14 mm versus 2.46 mm in wild-type neonates

abnormal long bone epiphyseal plate morphology ( J:109505 )

• there is a significant decrease in proliferating cells of the epiphyses (8.74% versus 13.03%)

abnormal long bone hypertrophic chondrocyte zone ( J:109505 )

• larger, irregularly shaped cells are dispersed among the normal, regular shaped hypertrophic cells

• mineral deposits are only observed in the lowermost zones of hyprertrophic cells instead of throughout the hypertrophic zone as is seen in wild-type

increased width of hypertrophic chondrocyte zone ( J:109505 )

• while the epiphyseal cartilage is reduced compared to wild-type, there is a disproportionate increase in the depth of type X positive cells that demarcate the hypertrophic zone

decreased long bone epiphyseal plate size ( J:109505 )

• the total epiphyseal cartilage is considerably reduced compared to controls

abnormal axial skeleton morphology ( J:109505 )

• the axial skeleton is shortened in neonates compared to controls

domed cranium ( J:109505 )

• is observed in these mice

limbs/digits/tail

short humerus ( J:109505 )

• humerus length of neonates is 2.10 mm versus 2.80 mm in wild-type neonates

short radius ( J:109505 )

• radius length of neonates is 2.30 mm versus 3.04 mm in wild-type neonates

short ulna ( J:109505 )

• is observed in neonates compared to controls

short femur ( J:109505 )

• femur length of neonates is 2.14 mm versus 2.46 mm in wild-type neonates

short limbs ( J:109505 )

• is observed in these mice

craniofacial

domed cranium ( J:109505 )

• is observed in these mice