Mouse Genome Informatics
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    Pax8tm1Pgr/Pax8tm1Pgr
either: (involves: 129S1/Sv * 129X1/SvJ) or (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
• homozygotes die around weaning time due to athyroidism
• early T4-substitution (initiated at P2) restores postnatal development and extends survival to adulthood
• most homozygotes die within the first weeks after birth and none survive weaning
• daily injections of T4 (20 ng/g/body weight) extend survival to old age with no overt deficits, even if initiated as late as P14
• however, complete recovery is not restored by immediate postnatal T4 substitution, indicating that some deficits result from prenatal T4 deficiency of the offspring
• homozygotes are born at the expected Mendelian frequency but die shortly after weaning due to a thyroid defect
• application of thyroxine extends survival up to 6 months

growth/size/body
• 22 of 43 athyroid homozygotes show outer ear abnormalities ranging from small pinnae to completely absent pinnae
• notably, outer-ear abnormalities are confined to minor size reductions of the pinnae and ear canals in adult T4-substituted homozygotes
• 22 of 43 homozygotes show outer ear abnormalities ranging from narrow ear canals to completely closed ear canals
• homozygotes exhibit growth retardation after one week of birth (J:47310)
• homozygotes display variable but obvious postnatal growth retardation relative to wild-type mice (J:116236)

endocrine/exocrine glands
• athyroid male homozygotes display a highly abnormal cellular composition of the anterior pituitary
• early T4-substitution (initiated at P2) restores pituitary hormone mRNA expression and anterior pituitary cellular composition to wild-type values at postpubertal age (>45 days)
• almost complete absence of lactotropes
• a severely reduced number of somatotropes
• hypertrophy and hyperplasia of the thyrotropes
• postpubertal T4-substituted male homozygotes (age >45 days) display a significantly reduced testis weight, not observed in prepubertal T4-substituted males (age 23-29 days) (J:117324)
• at E17 and at birth, mutant thyroids are composed almost completely of calcitonin-producing C-cells
• no thyroxine-producing follicular cells are detected
• at E11.5, the mutant thyroid diverticulum fails to expand laterally as in wild-type mice, and instead resembles that of E10.5 embryos
• at E12.5, follicular-cell precursors are not formed, as the collar-shaped structure is completely absent
• at E15.5, the only remaining thyroid structure is the ultimobranchial body
• at E11.5, the mutant thyroid diverticulum fails to expand laterally as in wild-type mice, and instead resembles that of E10.5 embryos
• homozygotes display a small thyroid gland
• in contrast, no structural defects are observed in the developing kidney or spinal cord

homeostasis/metabolism
• at 2 weeks of age, homozygotes display significantly reduced serum thyroxine levels relative to wild-type mice (J:47310)
• homozygotes lack detectable serum T4 levels at all postnatal test ages (J:116236)
• homozygotes lack detectable serum T3 levels at all postnatal test ages

hearing/vestibular/ear
• at P20-P21, athyroid homozygotes occasionally exhibit rudimentary kinocilia
• 22 of 43 athyroid homozygotes show outer ear abnormalities ranging from small pinnae to completely absent pinnae
• notably, outer-ear abnormalities are confined to minor size reductions of the pinnae and ear canals in adult T4-substituted homozygotes
• 22 of 43 homozygotes show outer ear abnormalities ranging from narrow ear canals to completely closed ear canals
• all athyroid homozygotes exhibit a ~7-day delay in inner ear development relative to wild-type mice
• at P12, the organ of Corti is still immature, Kolliker's organ is still present, the pillar cells have not elongated, and the tunnel of Corti remains closed
• at P16, the organ of Corti has developed, the pillars have elongated and the tunnel of Corti, as well as the inner sulcus have opened; however, the minor tectorial structures and marginal pillar cells are still present
• by P21, the tunnel of Corti and inner sulcus have enlarged, the spaces of Nuel around OHCs have formed but the tectorial membrane is still abnormally thick
• at P13, the mutant inner ear is still in the stage of Kolliker's organ without a tunnel of Corti
• at 2 weeks after birth, athyroid homozygotes display an immature organ of Corti at the light microscopy level
• in contrast, early TH-substituted homozygotes exhibit a mature organ of Corti at P15
• at P20-P21, athyroid homozygotes exhibit immature IHCs and OHCs over the entire apical surface, with numerous microvilli
• at P20-P21, athyroid homozygotes exhibit numerous, enlarged stereocilia over the apical surface of immature IHCs and OHCs
• at this ages, mutant supporting cells also display significantly more stereocilia on their apical surface than normal
• late T4-substituted homozygotes (P8 or later) exhibit disarray of stereovilli from both inner and outer cochlear hair cells
• the extent of structural disorder increases the later T4 substitution is initiated
• at P21, the apical ends of mutant OHC stereocilia are still covered by a contiguous membrane (""granular layer""), which is normally completely absent in wild-type mice at P20
• at P15, athyroid homozygotes exhibit prolonged efferent innervation of IHCs by olivocochlear fibers, in contrast to the developmental decline of efferent IHC innervation noted in wild-type mice
• at P14-P15, athyroid IHCs display an immature afferent synaptic organization, with higher numbers of ribbons and immature synaptic contacts (showing several ribbons) relative to mature wild-type IHCs where fewer and confined single ribbon synapses are observed
• early TH-substitution restores normal maturation of ribbon synapse morphology and function in IHCs of P14-P15 athyroid homozygotes
• late T4-substituted homozygotes (P8 or later) exhibit OHC loss, predominantly in the basal part of the cochlea
• at P21, homozygotes display abnormal persistence of marginal pillar cells, normally lost at P20 in wild-type mice
• at >P12, the mutant tectorial membrane is permanently thicker than normal with cavities in the center; minor tectorial structures persist through at least P16
• at P13, mutant tectorial membranes show an apical to basal decrease in thickness that is less evident in wild-type mice
• the tectorial membrane remains abnormally thick even when T4 substitution is initiated at P8 or later
• 20 of 31 athyroid homozygotes display abnormal middle ears with poorly calcified cartilaginous bulla, sometimes filled with a jelly-like substance
• notably, middle-ear abnormalities persist in 51 of 77 ears from T4-substituted homozygotes
• 20 of 31 homozygotes display malformations of the middle-ear ossicles
• mutant middle-ear ossicles are always calcified, never cartilaginous
• 20 of 31 homozygotes show a malformed stapes with an abnormal articulation to the oval window
• one of the crurae of the stapes is regularly missing or much thinner than normal
• the mutant stapes is occasionally immobile, fixed in the oval window
• 20 of 31 homozygotes display a malformed or absent stapedial artery
• 20 of 31 homozygotes display a malformed or absent stapedial artery
• in 20 of 31 homozygotes, the round window of the cochlea is often smaller or completely absent
• in contrast to wild-type IHCs which stop spontaneous spiking activity (i.e. generation of Ca2+ action potentials, APs) at P8, athyroid IHCs generate Ca2+ APs as late as at P14 (i.e. beyond the onset of hearing); however, no differences in amplitude and frequency of spontaneous Ca2+ APs are noted until P7 (J:119449)
• injection of small positive currents prolongs the period of spiking until P12 in wild-type IHCs and until P21 in athyroid IHCs, indicating persistence of induced spiking activity (J:119449)
• in athyroid IHCs, persistence of Ca2+ APs until P21 is due to (i) failure of downregulation of the Ca2+ current (ICa) at P13-P18, and (ii) failure of upregulation of the large-conductance Ca2+-activated K+ (BK) current due to lack of expression of IK,f (fast-activating potassium current carried by BK channels) at P12 or later (J:119449)
• specifically, Ca2+ currents are elevated 3-fold after P12 while the K+ current of athyroid IHCs is only ~43% that of wild-type IHCs at P16, with no differences in peak K+ currents noted at early neonatal stages (P2-P4) (J:119449)
• athyroid IHCs perform exocytosis until P21; however, exocytosis efficiency is significantly reduced in the third postnatal week (59% of wild-type), typical for immature, prehearing IHCs (J:119449)
• surprisingly, otoferlin protein (a key component in IHC exocytosis) is present in athyroid mouse IHCs at P12, but not expressed in IHCs of hypothyroid rats at P9 or P18 (J:119449)
• athyroid homozygotes display impaired maturation of presynaptic function in cochlear IHCs (J:119450)
• Ca2+ currents of athyroid IHCs are smaller than wild-type currents at P6-P8 but ~2.5-fold larger than those of wild-type IHCs at 2 weeks after birth, indicating delayed Ca2+ current upregulation and lack of downregulation up to P15 (J:119450)
• voltage dependence of Ca2+ current in athyroid IHCs is normal at P14-P16 but displays a slightly more hyperpolarized peak potential in athyroid IHCs at P6-P8 relative to wild-type IHCs (J:119450)
• early TH-substitution (initiated at birth) restores the Ca2+ current amplitudes of athyroid IHCs to wild-type values at P15 (J:119450)
• the efficiency of Ca2+ influx in triggering fast exocytosis of the readily releasable vesicle pool is reduced in athyroid IHCs at P14-P16 relative to mature wild-type IHCs (J:119450)
• notably, the efficiency of sustained exocytosis in P14-P16 athyroid IHCs exceeds that of immature wild-type IHCs (J:119450)
• despite substantial Ca2+ currents, little exocytosis is observed in athyroid IHCs at P6-P8 for all but very long stimulus durations (J:119450)
• early TH-substitution (initiated at birth) restores normal Ca2+ currents and exocytic capacitance changes of athyroid IHCs at P15, consistent with a partial restoration of hearing after TH substitution (J:119450)
• at P14-P16, athyroid IHCs lack large-conductance Ca2+-activated K+ currents and KCNQ4 currents, with abnormal persistence of Ca2+ action potentials (J:119450)
• P14-P16 athyroid IHCs display more depolarized resting potentials and immature passive electrical properties relative to wild-type IHCs (J:119450)
• even when T4 substitution is started at P1, ABR thresholds, measured at 6 weeks of age or more, are elevated by ~20 dB, and each day of delay in the start of T4 substitution results in an additional threshold loss of ~4 dB
• at P21, athyroid homozygotes exhibit no auditory brain stem responses (ABR) to sound at 130 dB SPL
• adult hearing can be nearly normalized by early postnatal substitution with thyroxine (T4); however, structural and functional restoration of hearing is incomplete

nervous system
• at P20-P21, athyroid homozygotes occasionally exhibit rudimentary kinocilia
• athyroid male homozygotes display a highly abnormal cellular composition of the anterior pituitary
• early T4-substitution (initiated at P2) restores pituitary hormone mRNA expression and anterior pituitary cellular composition to wild-type values at postpubertal age (>45 days)
• almost complete absence of lactotropes
• a severely reduced number of somatotropes
• hypertrophy and hyperplasia of the thyrotropes
• at P20-P21, athyroid homozygotes exhibit immature IHCs and OHCs over the entire apical surface, with numerous microvilli
• at P20-P21, athyroid homozygotes exhibit numerous, enlarged stereocilia over the apical surface of immature IHCs and OHCs
• at this ages, mutant supporting cells also display significantly more stereocilia on their apical surface than normal
• late T4-substituted homozygotes (P8 or later) exhibit disarray of stereovilli from both inner and outer cochlear hair cells
• the extent of structural disorder increases the later T4 substitution is initiated
• at P21, the apical ends of mutant OHC stereocilia are still covered by a contiguous membrane (""granular layer""), which is normally completely absent in wild-type mice at P20
• at P15, athyroid homozygotes exhibit prolonged efferent innervation of IHCs by olivocochlear fibers, in contrast to the developmental decline of efferent IHC innervation noted in wild-type mice
• at P14-P15, athyroid IHCs display an immature afferent synaptic organization, with higher numbers of ribbons and immature synaptic contacts (showing several ribbons) relative to mature wild-type IHCs where fewer and confined single ribbon synapses are observed
• early TH-substitution restores normal maturation of ribbon synapse morphology and function in IHCs of P14-P15 athyroid homozygotes
• late T4-substituted homozygotes (P8 or later) exhibit OHC loss, predominantly in the basal part of the cochlea
• in contrast to wild-type IHCs which stop spontaneous spiking activity (i.e. generation of Ca2+ action potentials, APs) at P8, athyroid IHCs generate Ca2+ APs as late as at P14 (i.e. beyond the onset of hearing); however, no differences in amplitude and frequency of spontaneous Ca2+ APs are noted until P7 (J:119449)
• injection of small positive currents prolongs the period of spiking until P12 in wild-type IHCs and until P21 in athyroid IHCs, indicating persistence of induced spiking activity (J:119449)
• in athyroid IHCs, persistence of Ca2+ APs until P21 is due to (i) failure of downregulation of the Ca2+ current (ICa) at P13-P18, and (ii) failure of upregulation of the large-conductance Ca2+-activated K+ (BK) current due to lack of expression of IK,f (fast-activating potassium current carried by BK channels) at P12 or later (J:119449)
• specifically, Ca2+ currents are elevated 3-fold after P12 while the K+ current of athyroid IHCs is only ~43% that of wild-type IHCs at P16, with no differences in peak K+ currents noted at early neonatal stages (P2-P4) (J:119449)
• athyroid IHCs perform exocytosis until P21; however, exocytosis efficiency is significantly reduced in the third postnatal week (59% of wild-type), typical for immature, prehearing IHCs (J:119449)
• surprisingly, otoferlin protein (a key component in IHC exocytosis) is present in athyroid mouse IHCs at P12, but not expressed in IHCs of hypothyroid rats at P9 or P18 (J:119449)
• athyroid homozygotes display impaired maturation of presynaptic function in cochlear IHCs (J:119450)
• Ca2+ currents of athyroid IHCs are smaller than wild-type currents at P6-P8 but ~2.5-fold larger than those of wild-type IHCs at 2 weeks after birth, indicating delayed Ca2+ current upregulation and lack of downregulation up to P15 (J:119450)
• voltage dependence of Ca2+ current in athyroid IHCs is normal at P14-P16 but displays a slightly more hyperpolarized peak potential in athyroid IHCs at P6-P8 relative to wild-type IHCs (J:119450)
• early TH-substitution (initiated at birth) restores the Ca2+ current amplitudes of athyroid IHCs to wild-type values at P15 (J:119450)
• the efficiency of Ca2+ influx in triggering fast exocytosis of the readily releasable vesicle pool is reduced in athyroid IHCs at P14-P16 relative to mature wild-type IHCs (J:119450)
• notably, the efficiency of sustained exocytosis in P14-P16 athyroid IHCs exceeds that of immature wild-type IHCs (J:119450)
• despite substantial Ca2+ currents, little exocytosis is observed in athyroid IHCs at P6-P8 for all but very long stimulus durations (J:119450)
• early TH-substitution (initiated at birth) restores normal Ca2+ currents and exocytic capacitance changes of athyroid IHCs at P15, consistent with a partial restoration of hearing after TH substitution (J:119450)
• at P14-P16, athyroid IHCs lack large-conductance Ca2+-activated K+ currents and KCNQ4 currents, with abnormal persistence of Ca2+ action potentials (J:119450)
• P14-P16 athyroid IHCs display more depolarized resting potentials and immature passive electrical properties relative to wild-type IHCs (J:119450)
• athyroid cochlear IHCs show failure of downregulation of Cav1.3 channels and upregulation of BK channels, leading to persistence of Ca2+ action potentials after P12 (normal onset of hearing) (J:119449)

skeleton
• 20 of 31 homozygotes display malformations of the middle-ear ossicles
• mutant middle-ear ossicles are always calcified, never cartilaginous
• 20 of 31 homozygotes show a malformed stapes with an abnormal articulation to the oval window
• one of the crurae of the stapes is regularly missing or much thinner than normal
• the mutant stapes is occasionally immobile, fixed in the oval window
• 20 of 31 homozygotes display a malformed or absent stapedial artery
• 20 of 31 homozygotes display a malformed or absent stapedial artery

cardiovascular system
• 20 of 31 homozygotes display a malformed or absent stapedial artery
• 20 of 31 homozygotes display a malformed or absent stapedial artery

craniofacial
• 20 of 31 homozygotes display malformations of the middle-ear ossicles
• mutant middle-ear ossicles are always calcified, never cartilaginous
• 20 of 31 homozygotes show a malformed stapes with an abnormal articulation to the oval window
• one of the crurae of the stapes is regularly missing or much thinner than normal
• the mutant stapes is occasionally immobile, fixed in the oval window
• 20 of 31 homozygotes display a malformed or absent stapedial artery
• 20 of 31 homozygotes display a malformed or absent stapedial artery
• 22 of 43 athyroid homozygotes show outer ear abnormalities ranging from small pinnae to completely absent pinnae
• notably, outer-ear abnormalities are confined to minor size reductions of the pinnae and ear canals in adult T4-substituted homozygotes
• 22 of 43 homozygotes show outer ear abnormalities ranging from narrow ear canals to completely closed ear canals

reproductive system
• postpubertal T4-substituted male homozygotes (age >45 days) display a significantly reduced testis weight, not observed in prepubertal T4-substituted males (age 23-29 days) (J:117324)
• 82% of T4-substituted female homozygotes develop a dilated, fluid-filled fallopian tube (hydrosalpinx) with a flattened mucosal layer within 6 months of age (J:129545)
• all T4-substituted female homozygotes show complete lack of endometrial structures (J:129545)
• all T4-substituted female homozygotes show only remnants of very thin, ligament-like myometrial tissue (J:129545)
• although cervical wall structure is normal, T4-substituted female homozygotes display a dilated fluid-filled cervical lumina (J:129545)
• at 6 months of age, all T4-substituted female homozygotes lack both uterine horns in the abdominal situs (J:129545)
• all T4-substituted female homozygotes fail to develop a functional uterus (J:129545)
• in contrast, the overall development of T4-substituted oviduct, cervix, and vagina appears unaffected (J:129545)
• at 6 months of age, all T4-substituted female homozygotes show only small remnants of a ligament-like tissue surrounded by fat at the site of uterus (J:129545)
• the small remnants of uterine tissue are histologically similar to smooth muscle cells, pointing to a myometrial origin (J:129545)
• the endometrial compartment and formation of a lumen are absent (J:129545)
• both at 7 weeks and at 6 months of age, all T4-substituted female homozygotes lack a vaginal opening (J:129545)
• although vaginal development is normal, the vagina of T4-substituted females is closed by a lucent membrane (J:129545)
• postpubertal T4-substituted male homozygotes (age >45 days) display a significantly smaller epididymis (J:117324)
• however, weights of the accessory sex glands (seminal vesicles and coagulating glands) of postpubertal rescued males are normal (J:117324)
• T4-treated female homozygotes fail to become pregnant when caged with fertile wild-type males (J:129545)
• however, no changes in mRNA expression of pituitary hormones or in the cellular composition of the anterior pituitary gland are noted in T4-treated (euthyroid) female homozygotes at 3 months of age (J:129545)
• also, all T4-substituted females display normal ovarian histology and ovulation and normal serum levels of 17beta-estrogen and progesterone at 6 months of age (J:129545)
• athyroid male homozygotes are infertile (J:117324)
• early T4-substitution (initiated at P2) restores development such that rescued homozygotes show no overt deficits; however, despite adequate T4 substitution, male homozygotes are unable to reproduce (J:117324)

embryogenesis
• T4-substituted female homozygotes show abnormal postnatal differentiation of the Mullerian duct, resulting in the absence of a functional uterus

cellular
• at P20-P21, athyroid homozygotes occasionally exhibit rudimentary kinocilia

Mouse Models of Human Disease
OMIM IDRef(s)
Hypothyroidism, Congenital, Nongoitrous, 2; CHNG2 218700 J:47310 , J:116236