hearing/vestibular/ear phenotype

• increased cochlear inner hair cell number
  • Normal - in contrast, the heterozygous outer hair cell population remains normal relative to wild-type mice
  (MGI Ref ID J:53290)
  • at P6, heterozygotes display occasional supernumerary inner hair cells throughout the organ of Corti; never observed in wild-type mice
  (MGI Ref ID J:53290)

nervous system phenotype

• increased cochlear inner hair cell number
  • Normal - in contrast, the heterozygous outer hair cell population remains normal relative to wild-type mice
  (MGI Ref ID J:53290)
  • at P6, heterozygotes display occasional supernumerary inner hair cells throughout the organ of Corti; never observed in wild-type mice
  (MGI Ref ID J:53290)

cellular phenotype

• abnormal cell proliferation
  • at E16, anti-PCNA staining of the organ of Corti indicates that proliferation of sensory cell progenitors abnormally continues after E14 (i.e. past the normal time of cell cycle withdrawal), leading to the appearance of supernumerary hair cells and supporting cells in mutant mice
  (MGI Ref ID J:53290)
  • at P6, PCNA-positive cells are no longer seen in Deiters' cell region as they are at E16, but appear in clusters in the region of Hensen's cells, lateral to the outermost row of OHCs, as well as in the pillar cell regions separating IHCs and OHCs
  (MGI Ref ID J:53290)
  • at E16, PCNA-positive cells are observed in the Deiters' cell region beneath the newly differentiated hair cells stained with anti-myosin VIIa
  (MGI Ref ID J:53290)
  • ting cells in mutant mice
  (MGI Ref ID J:53290)

mammalian phenotype

• behavior/neurological phenotype
  • Normal - no obvious behavioral defects related to vestibular function, such as circling or balance deficits, are observed
  (MGI Ref ID J:53290)

nervous system phenotype

• increased cochlear outer hair cell number
  • in homozygotes, OHC numbers are increased by a mean of 36% relative to wild-type mice
  (MGI Ref ID J:53290)
  • at P6, homozygotes contain four, partly disorganized, rows of cochlear outer hair cells (OHCs) instead of the expected three rows of OHCs seen in wild-type mice
  (MGI Ref ID J:53290)

• increased cochlear inner hair cell number
  • at P6, the mutant inner row contains a partly disorganized line of at most two hair cells, whereas wild-type mice normally contain a single row of inner hair cells
  (MGI Ref ID J:53290)
  • in homozygotes, IHC numbers are increased by a mean of 23% relative to wild-type mice
  (MGI Ref ID J:53290)

• increased cochlear hair cell number
  • homozygotes develop supernumerary hair cells in both the inner and outer rows of hair cells
  (MGI Ref ID J:53290)

growth/size/body region phenotype

• increased body size
  • homozygotes are larger than wild-type littermates as a result of multiorgan hyperplasia
  (MGI Ref ID J:53290)

hearing/vestibular/ear phenotype

• abnormal organ of Corti morphology
  • continued presence of proliferating cells in the postnatal organ of Corti, as well as abnormal persistence of Cdkn1b expression in mature supporting cells indicate a role for Cdkn1b in maintaining these cells in a quiescent state
  (MGI Ref ID J:53290)
  • at P6, homozygotes exhibit hyperplasia of the organ of Corti
  (MGI Ref ID J:53290)

• abnormal pillar cell morphology
  • at P6, homozygotes display supernumerary cells in the pillar cell region of the organ of Corti, where normally one inner pillar and one outer pillar cells are present in wild-type mice
  (MGI Ref ID J:53290)

• increased cochlear outer hair cell number
  • in homozygotes, OHC numbers are increased by a mean of 36% relative to wild-type mice
  (MGI Ref ID J:53290)
  • at P6, homozygotes contain four, partly disorganized, rows of cochlear outer hair cells (OHCs) instead of the expected three rows of OHCs seen in wild-type mice
  (MGI Ref ID J:53290)

• increased cochlear inner hair cell number
  • at P6, the mutant inner row contains a partly disorganized line of at most two hair cells, whereas wild-type mice normally contain a single row of inner hair cells
  (MGI Ref ID J:53290)
  • in homozygotes, IHC numbers are increased by a mean of 23% relative to wild-type mice
  (MGI Ref ID J:53290)

• increased organ of Corti supporting cell number
  • homozygotes develop an excess number of supporting cells, including pillar cells, separating IHCs from OHCs and occupying the area of the tunnel of Corti
  (MGI Ref ID J:53290)

• impaired hearing
  • at 10 weeks of age, homozygotes are severely hearing-impaired
  (MGI Ref ID J:53290)

• increased cochlear hair cell number
  • homozygotes develop supernumerary hair cells in both the inner and outer rows of hair cells
  (MGI Ref ID J:53290)

• increased or absent threshold for auditory brainstem response
  • at 10 weeks of age, homozygotes display a significantly elevated mean, click-evoked, ABR threshold (77 db SPL) relative to age-matched wild-type mice (20 db SPL)
  (MGI Ref ID J:53290)

cellular phenotype

• increased T cell proliferation
  • thymoblasts and splenic T cells have an increase in percentage of S phase cells and a 3-4-fold increase in cyclin E-associated kinase activity, indicating increased cell proliferation
  (MGI Ref ID J:33400)

growth/size/body region phenotype

• spleen hyperplasia
  • becomes evident by 4 weeks of age
  (MGI Ref ID J:33400)

• enlarged spleen
  • disproportionately enlarged
  (MGI Ref ID J:33400)

• increased body weight
  • body weight increase becomes evident between 2-3 weeks of age, is maximal by 10 weeks of age, and is maintained throughout adulthood and is partly attributable to enlargement of all internal organs, however do not have an increase in body fat amount
  (MGI Ref ID J:33400)

hematopoietic system phenotype

• spleen hyperplasia
  • becomes evident by 4 weeks of age
  (MGI Ref ID J:33400)

• enlarged thymus
  • disproportionately enlarged
  (MGI Ref ID J:33400)

• enlarged spleen
  • disproportionately enlarged
  (MGI Ref ID J:33400)

• increased T cell proliferation
  • thymoblasts and splenic T cells have an increase in percentage of S phase cells and a 3-4-fold increase in cyclin E-associated kinase activity, indicating increased cell proliferation
  (MGI Ref ID J:33400)

• thymus hyperplasia
  • 3-fold increase in the number of thymocytes, however development of thymocytes is normal
  (MGI Ref ID J:33400)
  • becomes evident by 4 weeks of age
  (MGI Ref ID J:33400)

• abnormal definitive hematopoiesis
  • increase in the number of granulocyte-macrophage, early and late erythroid progenitors, and megakaryotic progenitors in both the marrow and spleen
  (MGI Ref ID J:33400)

• abnormal thymus morphology
  (MGI Ref ID J:33400)

• abnormal spleen morphology
  (MGI Ref ID J:33400)

immune system phenotype

• enlarged spleen
  • disproportionately enlarged
  (MGI Ref ID J:33400)

• enlarged thymus
  • disproportionately enlarged
  (MGI Ref ID J:33400)

• spleen hyperplasia
  • becomes evident by 4 weeks of age
  (MGI Ref ID J:33400)

• thymus hyperplasia
  • 3-fold increase in the number of thymocytes, however development of thymocytes is normal
  (MGI Ref ID J:33400)
  • becomes evident by 4 weeks of age
  (MGI Ref ID J:33400)

• abnormal spleen morphology
  (MGI Ref ID J:33400)

• increased T cell proliferation
  • thymoblasts and splenic T cells have an increase in percentage of S phase cells and a 3-4-fold increase in cyclin E-associated kinase activity, indicating increased cell proliferation
  (MGI Ref ID J:33400)

• abnormal thymus morphology
  (MGI Ref ID J:33400)

liver/biliary system phenotype

• abnormal hepatocyte morphology
  • average of 23% increase in hepatocyte cell density
  (MGI Ref ID J:33400)

mortality/aging

• premature death
  • Background Sensitivity - no indication of early mortality at 9 months of age on the mixed 129/Sv and C57BL/6J background, however on a 129/Sv background, majority die with massively enlarged pituitary tumors
  (MGI Ref ID J:33400)

neoplasm

• increased pituitary adenoma incidence
  • adenomatous, neoplastic transformation of the pars intermedia
  (MGI Ref ID J:33400)

nervous system phenotype

• abnormal cerebral cortex morphology
  • about 30% increase in neuronal cell density in the cerebral cortex
  (MGI Ref ID J:33400)

• increased pituitary adenoma incidence
  • adenomatous, neoplastic transformation of the pars intermedia
  (MGI Ref ID J:33400)

• enlarged pituitary gland
  • disproportionately enlarged
  (MGI Ref ID J:33400)

• pituitary gland hyperplasia
  • gross hyperplasia becomes evident at 8-10 weeks of age
  (MGI Ref ID J:33400)

• abnormal epithalamus morphology
  • about 30% increase in neuronal cell density in the habenular nucleus
  (MGI Ref ID J:33400)

• abnormal hippocampus morphology
  • about 30% increase in neuronal cell density in the hippocampus
  (MGI Ref ID J:33400)

reproductive system phenotype

• female infertility
  • females do not become pregnant, however, exogenous administration of gonadotropins induced ovulation, differentiation of the corpora lutea, and early development of viable embryos, with embryos implanting but not developing to term
  (MGI Ref ID J:33400)

• absent corpus luteum
  • secondary ovarian follicles develop but do not progress to form corpora lutea
  (MGI Ref ID J:33400)

vision/eye phenotype

• abnormal retinal neuronal layer morphology
  • loss of the normally sharp boundary between the inner and outer nuclear layer
  (MGI Ref ID J:33400)

• disorganized retinal layers
  • subtle disorganization of the retina
  (MGI Ref ID J:33400)

endocrine/exocrine gland phenotype

• thymus hyperplasia
  • becomes evident by 4 weeks of age
  (MGI Ref ID J:33400)
  • 3-fold increase in the number of thymocytes, however development of thymocytes is normal
  (MGI Ref ID J:33400)

• abnormal thymus morphology
  (MGI Ref ID J:33400)

• enlarged thymus
  • disproportionately enlarged
  (MGI Ref ID J:33400)

• enlarged pituitary gland
  • disproportionately enlarged
  (MGI Ref ID J:33400)

• increased pituitary adenoma incidence
  • adenomatous, neoplastic transformation of the pars intermedia
  (MGI Ref ID J:33400)

• pituitary gland hyperplasia
  • gross hyperplasia becomes evident at 8-10 weeks of age
  (MGI Ref ID J:33400)

• absent corpus luteum
  • secondary ovarian follicles develop but do not progress to form corpora lutea
  (MGI Ref ID J:33400)

cellular phenotype

• abnormal neuron differentiation
  • cortex of mutant shows fewer neurons born on E14.5 that express differentiation markers at E17.5
  (MGI Ref ID J:109091)
  • reduction in differentiation is most prominent in VZ/SVZ
  (MGI Ref ID J:109091)

• abnormal neuronal migration
  • greater numbers of cells accumulates in the ventricular zone (VZ) and subventricular zone (SVZ) in mutants
  (MGI Ref ID J:109091)
  • radial migration is impaired in mutant cortices
  (MGI Ref ID J:109091)
  • defect in cortical neuronal migration is observed at E17.5; fewer cells reach the cortical plate in mutants compared to wild-type
  (MGI Ref ID J:109091)

homeostasis/metabolism phenotype

• increased incidence of tumors by chemical induction
  • increase in incidence of urethane-induced lung tumors compared to wild-type, with more large tumors than in heterozygotes
  (MGI Ref ID J:103819)
  • 100% penetrance of pituitary adenomas and harderian gland tumors after 20 weeks of urethane treatment, as well as increased incidence of liver hemangiomas, uterine tumors and ovarian granulose cell tumors
  (MGI Ref ID J:103819)

immune system phenotype

• enlarged spleen
  • spleens are enlarged when recipients receive bone marrow cells from wild-type or mutant donors
  (MGI Ref ID J:107588)

• enlarged thymus
  • Cdkn1b-deficient mice develop hyperplastic thymuses when receiving bone marrow from wild-type or mutant donors
  (MGI Ref ID J:107588)

• spleen hypoplasia
  • Cdkn1b-deficient mice show hypercellular spleens when receiving transplants of bone marrow from mutant or wild-type mice
  (MGI Ref ID J:107588)

neoplasm

• increased incidence of tumors by chemical induction
  • increase in incidence of urethane-induced lung tumors compared to wild-type, with more large tumors than in heterozygotes
  (MGI Ref ID J:103819)
  • 100% penetrance of pituitary adenomas and harderian gland tumors after 20 weeks of urethane treatment, as well as increased incidence of liver hemangiomas, uterine tumors and ovarian granulose cell tumors
  (MGI Ref ID J:103819)

nervous system phenotype

• abnormal neuron differentiation
  • cortex of mutant shows fewer neurons born on E14.5 that express differentiation markers at E17.5
  (MGI Ref ID J:109091)
  • reduction in differentiation is most prominent in VZ/SVZ
  (MGI Ref ID J:109091)

• abnormal neuronal migration
  • greater numbers of cells accumulates in the ventricular zone (VZ) and subventricular zone (SVZ) in mutants
  (MGI Ref ID J:109091)
  • defect in cortical neuronal migration is observed at E17.5; fewer cells reach the cortical plate in mutants compared to wild-type
  (MGI Ref ID J:109091)
  • radial migration is impaired in mutant cortices
  (MGI Ref ID J:109091)

endocrine/exocrine gland phenotype

• enlarged thymus
  • Cdkn1b-deficient mice develop hyperplastic thymuses when receiving bone marrow from wild-type or mutant donors
  (MGI Ref ID J:107588)

growth/size/body region phenotype

• enlarged spleen
  • spleens are enlarged when recipients receive bone marrow cells from wild-type or mutant donors
  (MGI Ref ID J:107588)

hematopoietic system phenotype

• enlarged spleen
  • spleens are enlarged when recipients receive bone marrow cells from wild-type or mutant donors
  (MGI Ref ID J:107588)

• enlarged thymus
  • Cdkn1b-deficient mice develop hyperplastic thymuses when receiving bone marrow from wild-type or mutant donors
  (MGI Ref ID J:107588)

• spleen hypoplasia
  • Cdkn1b-deficient mice show hypercellular spleens when receiving transplants of bone marrow from mutant or wild-type mice
  (MGI Ref ID J:107588)

homeostasis/metabolism phenotype

• increased incidence of tumors by chemical induction
  • increased incidence of liver hemangiomas, uterine tumors, and ovarian granulose cell tumors after 20 weeks of urethane treatment, but less than in homozygotes
  (MGI Ref ID J:103819)
  • similar increase in the incidence of urethane-induced lung tumors as homozygotes, with more large tumors than in wild-type
  (MGI Ref ID J:103819)

neoplasm

• increased incidence of tumors by chemical induction
  • increased incidence of liver hemangiomas, uterine tumors, and ovarian granulose cell tumors after 20 weeks of urethane treatment, but less than in homozygotes
  (MGI Ref ID J:103819)
  • similar increase in the incidence of urethane-induced lung tumors as homozygotes, with more large tumors than in wild-type
  (MGI Ref ID J:103819)