Mouse Genome Informatics
hm
    Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• 50% die within the first 4-5 months of life

growth/size
• weight is normal during the first week after birth
• weight gain is slower from the second week on

behavior/neurological
• eventually absent
• normal at 1-2 months of age but diminishing thereafter and eventually disappears
• cerebellar ataxia possibly causing the observed abnormal gait
• widened stance
• minimal alternation between right and left side
• frequently fail to fully lift each foot between steps
• in older animals

hearing/vestibular/ear
• eventually the near complete loss of hair cells, first the outer hair cells and then the inner hair cells
• enlarged blood vessels in the stria vascularis
• no identifiable blood vessels at 11 months of age
• almost completely degenerated by 11 months of age
• elevated auditory thresholds are observed; in one case, the auditory brainstem response threshold is at least 40 dB higher than the average control value of ~60 dB
• hearing loss does not require loss of primary sensory cells, either the outer or inner hair cells

nervous system
• eventually the near complete loss of hair cells, first the outer hair cells and then the inner hair cells
• vasculature of the cerebellum is noticeably sparser than controls at 30 days of age and very sparse and irregular at 6 months
• progressive cerebellar degeneration starting around 3rd postnatal week
• dramatic loss of Purkinje cells and vacuolization
• apoptosis not observed in Purkinje cells but cells are lost progressively through adulthood
• dramatic loss of granule cells and vacuolization
• massive apoptosis of granule cells starting between 14 and 19 days of age
• 50X more apoptosis in the cerebellum at 19 days of age
• apoptosis drops off greatly at 30 days of age
• hypocellular cerebellum but cerebellar architecture normal
• abnormal astroglial activation in adults

cardiovascular system
• the two intraretinal capillary beds fail to develop
• major arteries and veins on the retina are enlarged and tortuous
• arteriolar arborization is diminished
• increased density of small vessels in nerve fiber layer
• many retinal blood vessels are fenestrated
• enlarged blood vessels in the stria vascularis
• no identifiable blood vessels at 11 months of age
• female homozygotes display disrupted vascular development of the corpora luteum
• markers of vascular cell function are reduced in ovaries of mutant female mice following natural mating
• small hemorrhages frequent in cerebellum
• small hemorrhages frequent in retina

vision/eye
• the two intraretinal capillary beds fail to develop
• major arteries and veins on the retina are enlarged and tortuous
• arteriolar arborization is diminished
• increased density of small vessels in nerve fiber layer
• many retinal blood vessels are fenestrated
• small hemorrhages frequent in retina
• hyaloid blood vessels fail to regress or regression is delayed 1-2 weeks

digestive/alimentary system
• loss of skeletal muscle on lower 1/4 of esophagous to as much as the entire esophagus
• no motor end plates along the lower portion of the esophagus
• desquamination of the esophageal epithelium
• progressive enlargement of the esophagus apparent at 8 days of age but not at birth
• defective esophageal peristalsis
• defective function of the gastric sphincter

muscle
• muscle fibers with smaller diameter but otherwise normal

pigmentation
• light black or silver coat color

reproductive system
N
• adult female homozygotes exhibit normal mating behavior relative to wild-type and heterozygous littermates (J:115734)
• following superovulation, female homozygotes produce an equal number of fertilized oocytes as their wild-type and heterozygous littermates (J:115734)
• immature mutant ovaries show normal follicular development and normal responses to gonadotropin stimulation during development to the preovulatory stage (J:115734)
• at 8 weeks of age, corpora lutea are variably present or absent in ovaries of some female mutant mice (J:115734)
• analysis of mutant ovaries from timed mating pairs shows that by day 7.5 pc, corpora lutea are not discernible, indicating that formation of functional corpora lutea is impaired (J:115734)
• on day 1.5 pc, mutant corpora lutea exhibit a thick, dense collagen IV network that is significantly less filamentous and punctate than that observed in wild-type corpora lutea, suggesting that vessel arborization is reduced during luteinization (J:115734)
• on day 1.5 pc, mutant corpora lutea exhibit clear signs of apoptosis, as indicated by the presence of activated caspase 3 (J:115734)
• whereas luteal cells in day 5.5 pregnant wild-type ovaries display cellular hypertrophy, luteal cells in day 5.5 non-pregnant mutant ovaries appear disorganized and display a lower cytoplasmic to nuclear ratio (J:115734)
• in mutant ovaries, expression of luteal cell-specific mRNAs is reduced as early as day 1.5 pc and remains low on day 5.5 pc (J:115734)
• after natural mating, some female homozygotes exhibit absence of corpora lutea (J:115734)
• analysis of ovaries from timed mating pairs indicates that female homozygotes exhibit no implantation sites on days 5.5 and 7.5 pc (J:115734)
• when mated to wild-type males, female homozygotes fail to become pregnant and produce offspring (J:115734)
• mutant ovaries collected at days 1.5, 5.5, and 7.5 pc display an altered histological appearance, reduced expression luteal cell-specific mRNAs, and distinct structural abnormalities within the vascular network, indicative of impaired luteal cell function (J:115734)
• preliminary observations suggest that male homozygotes appear to be infertile (J:115734)

homeostasis/metabolism
• on day 1.5 post-coitum (pc), serum progesterone levels are reduced by 50% in female mutant mice relative to wild-type females, and decrease dramatically on days 5.5 and 7.5 pc with no evidence of implantation
• in contrast, no significant differences are observed in serum prolactin levels between female mutant and wild-type mice on day 5.5 pc

endocrine/exocrine glands
• at 8 weeks of age, corpora lutea are variably present or absent in ovaries of some female mutant mice (J:115734)
• analysis of mutant ovaries from timed mating pairs shows that by day 7.5 pc, corpora lutea are not discernible, indicating that formation of functional corpora lutea is impaired (J:115734)
• on day 1.5 pc, mutant corpora lutea exhibit a thick, dense collagen IV network that is significantly less filamentous and punctate than that observed in wild-type corpora lutea, suggesting that vessel arborization is reduced during luteinization (J:115734)
• on day 1.5 pc, mutant corpora lutea exhibit clear signs of apoptosis, as indicated by the presence of activated caspase 3 (J:115734)
• whereas luteal cells in day 5.5 pregnant wild-type ovaries display cellular hypertrophy, luteal cells in day 5.5 non-pregnant mutant ovaries appear disorganized and display a lower cytoplasmic to nuclear ratio (J:115734)
• in mutant ovaries, expression of luteal cell-specific mRNAs is reduced as early as day 1.5 pc and remains low on day 5.5 pc (J:115734)
• after natural mating, some female homozygotes exhibit absence of corpora lutea (J:115734)

integument
• light black or silver coat color

cellular
• whereas luteal cells in day 5.5 pregnant wild-type ovaries display cellular hypertrophy, luteal cells in day 5.5 non-pregnant mutant ovaries appear disorganized and display a lower cytoplasmic to nuclear ratio (J:115734)
• in mutant ovaries, expression of luteal cell-specific mRNAs is reduced as early as day 1.5 pc and remains low on day 5.5 pc (J:115734)

Mouse Models of Human Disease
OMIM IDRef(s)
Norrie Disease; ND 310600 J:107732