Phenotypes associated with this allele

• Allele Symbol: Cdkn1b^tm1Mlf
• Allele Name: targeted mutation 1, Matthew Fero
• Allele ID: MGI:1857146
• Summary: 25 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf	involves: 129S4/SvJaeSor	MGI:3611803
hm2	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf	involves: 129S4/SvJaeSor * C57BL/6J	MGI:2175761
hm3	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf	involves: 129S4/SvJaeSor * C57BL/6NHsd	MGI:3719053
ht4	Cdkn1b^tm1Mlf/Cdkn1b^+	involves: 129S4/SvJaeSor	MGI:3611804
ht5	Cdkn1b^tm1Mlf/Cdkn1b^+	involves: 129S4/SvJaeSor * C57BL/6NHsd	MGI:3719055
cn6	Cdkn1b^tm1Mlf/Cdkn1b^+ Crebbp^tm1Jvd/Crebbp^tm1Jvd Tg(MMTV-cre)4Mam/0	involves: 129 * C57BL/6 * CBA * FVB	MGI:3618584
cn7	Ccnd3^tm1Pisc/Ccnd3^tm1Pisc Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Rb1^tm2Brn/Rb1^tm2Brn Tg(Mx1-cre)1Cgn/0	involves: 129S4/SvJaeSor * C57BL/6 * CBA	MGI:5468653
cx8	Ccnd1^tm1Dsn/Ccnd1^tm1Dsn Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf	involves: 129 * C57BL/6	MGI:3044974
cx9	Cdkn1b^tm1Mlf/Cdkn1b^+ Vsx2^tm1.1Eml/Vsx2^tm1.1Eml	involves: 129 * C57BL/6	MGI:5449369
cx10	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Rbx1^Gt(XB674)Byg/Rbx1^Gt(XB674)Byg	involves: 129P2/OlaHsd * 129S4/SvJaeSor * C57BL/6J	MGI:3842439
cx11	Cdkn1b^tm1Mlf/Cdkn1b^+ Myc^tm1Atp/Myc^+	involves: 129P2/OlaHsd * 129S4/SvJaeSor * FVB/N	MGI:3811822
cx12	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Myc^tm1Atp/Myc^tm1Atp	involves: 129P2/OlaHsd * 129S4/SvJaeSor * FVB/N	MGI:3811823
cx13	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Myc^tm1Atp/Myc^+	involves: 129P2/OlaHsd * 129S4/SvJaeSor * FVB/N	MGI:3811821
cx14	Cdkn1b^tm1Mlf/Cdkn1b^+ Ptch1^tm1Mps/Ptch1^+	involves: 129S1/Sv * 129S4/SvJaeSor * 129X1/SvJ * C57BL/6	MGI:5544754
cx15	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Ptch1^tm1Mps/Ptch1^+	involves: 129S1/Sv * 129S4/SvJaeSor * 129X1/SvJ * C57BL/6	MGI:5544755
cx16	Cdkn1a^tm1Tyj/Cdkn1a^tm1Tyj Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf	involves: 129S2/SvPas * 129S4/SvJaeSor	MGI:4420782
cx17	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Tg(KRT5-CDK4)2303Mlrp/0	involves: 129S4/SvJae * C57BL/6 * FVB * SENCAR * SSIN	MGI:3624687
cx18	Ccnd3^tm1Pisc/Ccnd3^tm1Pisc Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf	involves: 129S4/SvJaeSor	MGI:5468651
cx19	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Trp53^tm1Brd/Trp53^tm1Brd	involves: 129S4/SvJaeSor * 129S7/SvEvBrd * C57BL/6J	MGI:3037841
cx20	Cdkn1b^tm1Mlf/Cdkn1b^+ Tg(TG-TPR/NTRK1)#Rstn/0	involves: 129S4/SvJaeSor * C3H * C57BL/6 * C57BL/6J	MGI:5581427
cx21	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Tg(TG-TPR/NTRK1)#Rstn/0	involves: 129S4/SvJaeSor * C3H * C57BL/6 * C57BL/6J	MGI:5581426
cx22	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Nkx3-1^tm1.1Saa/Nkx3-1^tm1.1Saa	involves: 129S4/SvJaeSor * C57BL/6 * FVB/N	MGI:3046061
cx23	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Tg(MMTV-vHaras)SH1Led/0	involves: 129S4/SvJaeSor * C57BL/6J * CD-1	MGI:2653622
cx24	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Cdkn2d^tm1Maro/Cdkn2d^tm1Maro	involves: 129X1/SvJ * C57BL/6	MGI:2662503
cx25	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Trp53^tm1Brd/Trp53^tm1Brd	involves: C3H * C57BL/6J * NIH	MGI:3037835

Genotype
MGI:3611803

hm1

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
• Genetic Background: involves: 129S4/SvJaeSor

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

nervous system

abnormal neuron differentiation ( J:109091 )

• cortex of mutant shows fewer neurons born on E14.5 that express differentiation markers at E17.5

• reduction in differentiation is most prominent in VZ/SVZ

abnormal neuronal migration ( J:109091 )

• defect in cortical neuronal migration is observed at E17.5; fewer cells reach the cortical plate in mutants compared to wild-type

• greater numbers of cells accumulates in the ventricular zone (VZ) and subventricular zone (SVZ) in mutants

• radial migration is impaired in mutant cortices

neoplasm

increased incidence of tumors by chemical induction ( J:103819 )

• increase in incidence of urethane-induced lung tumors compared to wild-type, with more large tumors than in heterozygotes

• 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

immune system

enlarged thymus ( J:107588 )

• Cdkn1b-deficient mice develop hyperplastic thymuses when receiving bone marrow from wild-type or mutant donors

enlarged spleen ( J:107588 )

• spleens are enlarged when recipients receive bone marrow cells from wild-type or mutant donors

spleen hypoplasia ( J:107588 )

• Cdkn1b-deficient mice show hypercellular spleens when receiving transplants of bone marrow from mutant or wild-type mice

hematopoietic system

enlarged thymus ( J:107588 )

• Cdkn1b-deficient mice develop hyperplastic thymuses when receiving bone marrow from wild-type or mutant donors

enlarged spleen ( J:107588 )

• spleens are enlarged when recipients receive bone marrow cells from wild-type or mutant donors

spleen hypoplasia ( J:107588 )

• Cdkn1b-deficient mice show hypercellular spleens when receiving transplants of bone marrow from mutant or wild-type mice

homeostasis/metabolism

increased incidence of tumors by chemical induction ( J:103819 )

• increase in incidence of urethane-induced lung tumors compared to wild-type, with more large tumors than in heterozygotes

• 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

cellular

abnormal neuron differentiation ( J:109091 )

• cortex of mutant shows fewer neurons born on E14.5 that express differentiation markers at E17.5

• reduction in differentiation is most prominent in VZ/SVZ

abnormal neuronal migration ( J:109091 )

• defect in cortical neuronal migration is observed at E17.5; fewer cells reach the cortical plate in mutants compared to wild-type

• greater numbers of cells accumulates in the ventricular zone (VZ) and subventricular zone (SVZ) in mutants

• radial migration is impaired in mutant cortices

endocrine/exocrine glands

enlarged thymus ( J:107588 )

• Cdkn1b-deficient mice develop hyperplastic thymuses when receiving bone marrow from wild-type or mutant donors

growth/size/body

enlarged spleen ( J:107588 )

• spleens are enlarged when recipients receive bone marrow cells from wild-type or mutant donors

Genotype
MGI:2175761

hm2

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
• Genetic Background: involves: 129S4/SvJaeSor * C57BL/6J

mortality/aging

premature death ( J:33400 )

• 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

growth/size/body

increased body weight ( J:33400 )

• 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

enlarged spleen ( J:33400 )

• disproportionately enlarged

spleen hyperplasia ( J:33400 )

• becomes evident by 4 weeks of age

neoplasm

increased pituitary adenoma incidence ( J:33400 )

• adenomatous, neoplastic transformation of the pars intermedia

endocrine/exocrine glands

enlarged pituitary gland ( J:33400 )

• disproportionately enlarged

pituitary gland hyperplasia ( J:33400 )

• gross hyperplasia becomes evident at 8-10 weeks of age

abnormal thymus morphology ( J:33400 )

enlarged thymus ( J:33400 )

• disproportionately enlarged

thymus hyperplasia ( J:33400 )

• becomes evident by 4 weeks of age

• 3-fold increase in the number of thymocytes, however development of thymocytes is normal

absent corpus luteum ( J:33400 )

♀ • secondary ovarian follicles develop but do not progress to form corpora lutea

increased pituitary adenoma incidence ( J:33400 )

• adenomatous, neoplastic transformation of the pars intermedia

immune system

increased T cell proliferation ( J:33400 )

• 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

abnormal thymus morphology ( J:33400 )

enlarged thymus ( J:33400 )

• disproportionately enlarged

thymus hyperplasia ( J:33400 )

• becomes evident by 4 weeks of age

• 3-fold increase in the number of thymocytes, however development of thymocytes is normal

abnormal spleen morphology ( J:33400 )

enlarged spleen ( J:33400 )

• disproportionately enlarged

spleen hyperplasia ( J:33400 )

• becomes evident by 4 weeks of age

hematopoietic system

increased T cell proliferation ( J:33400 )

• 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

abnormal thymus morphology ( J:33400 )

enlarged thymus ( J:33400 )

• disproportionately enlarged

thymus hyperplasia ( J:33400 )

• becomes evident by 4 weeks of age

• 3-fold increase in the number of thymocytes, however development of thymocytes is normal

abnormal definitive hematopoiesis ( J:33400 )

• increase in the number of granulocyte-macrophage, early and late erythroid progenitors, and megakaryotic progenitors in both the marrow and spleen

abnormal spleen morphology ( J:33400 )

enlarged spleen ( J:33400 )

• disproportionately enlarged

spleen hyperplasia ( J:33400 )

• becomes evident by 4 weeks of age

liver/biliary system

abnormal hepatocyte morphology ( J:33400 )

• average of 23% increase in hepatocyte cell density

reproductive system

absent corpus luteum ( J:33400 )

♀ • secondary ovarian follicles develop but do not progress to form corpora lutea

female infertility ( J:33400 )

♀ • 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

vision/eye

abnormal retina neuronal layer morphology ( J:33400 )

• loss of the normally sharp boundary between the inner and outer nuclear layer

disorganized retina layers ( J:33400 )

• subtle disorganization of the retina

nervous system

enlarged pituitary gland ( J:33400 )

• disproportionately enlarged

pituitary gland hyperplasia ( J:33400 )

• gross hyperplasia becomes evident at 8-10 weeks of age

increased pituitary adenoma incidence ( J:33400 )

• adenomatous, neoplastic transformation of the pars intermedia

abnormal epithalamus morphology ( J:33400 )

• about 30% increase in neuronal cell density in the habenular nucleus

abnormal hippocampus morphology ( J:33400 )

• about 30% increase in neuronal cell density in the hippocampus

abnormal cerebral cortex morphology ( J:33400 )

• about 30% increase in neuronal cell density in the cerebral cortex

cellular

increased T cell proliferation ( J:33400 )

• 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

Genotype
MGI:3719053

hm3

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
• Genetic Background: involves: 129S4/SvJaeSor * C57BL/6NHsd

growth/size/body

increased body size ( J:53290 )

• homozygotes are larger than wild-type littermates as a result of multiorgan hyperplasia

hearing/vestibular/ear

abnormal organ of Corti morphology ( J:53290 )

• at P6, homozygotes exhibit hyperplasia of the organ of Corti

• 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

increased cochlear hair cell number ( J:53290 )

• homozygotes develop supernumerary hair cells in both the inner and outer rows of hair cells

increased cochlear inner hair cell number ( J:53290 )

• 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

• in homozygotes, IHC numbers are increased by a mean of 23% relative to wild-type mice

increased cochlear outer hair cell number ( 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

• in homozygotes, OHC numbers are increased by a mean of 36% relative to wild-type mice

increased organ of Corti supporting cell number ( J:53290 )

• homozygotes develop an excess number of supporting cells, including pillar cells, separating IHCs from OHCs and occupying the area of the tunnel of Corti

abnormal pillar cell morphology ( J:53290 )

• 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

increased or absent threshold for auditory brainstem response ( J:53290 )

• 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)

impaired hearing ( J:53290 )

• at 10 weeks of age, homozygotes are severely hearing-impaired

nervous system

increased cochlear hair cell number ( J:53290 )

• homozygotes develop supernumerary hair cells in both the inner and outer rows of hair cells

increased cochlear inner hair cell number ( J:53290 )

• 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

• in homozygotes, IHC numbers are increased by a mean of 23% relative to wild-type mice

increased cochlear outer hair cell number ( 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

• in homozygotes, OHC numbers are increased by a mean of 36% relative to wild-type mice

cellular

abnormal cell proliferation ( J:53290 )

• 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

• at E16, PCNA-positive cells are observed in the Deiters' cell region beneath the newly differentiated hair cells stained with anti-myosin VIIa

• 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

behavior/neurological

behavior/neurological phenotype ( J:53290 )

N • no obvious behavioral defects related to vestibular function, such as circling or balance deficits, are observed

Genotype
MGI:3611804

ht4

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b⁺
• Genetic Background: involves: 129S4/SvJaeSor

neoplasm

increased incidence of tumors by chemical induction ( J:103819 )

• similar increase in the incidence of urethane-induced lung tumors as homozygotes, with more large tumors than in wild-type

• increased incidence of liver hemangiomas, uterine tumors, and ovarian granulose cell tumors after 20 weeks of urethane treatment, but less than in homozygotes

homeostasis/metabolism

increased incidence of tumors by chemical induction ( J:103819 )

• similar increase in the incidence of urethane-induced lung tumors as homozygotes, with more large tumors than in wild-type

• increased incidence of liver hemangiomas, uterine tumors, and ovarian granulose cell tumors after 20 weeks of urethane treatment, but less than in homozygotes

Genotype
MGI:3719055

ht5

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b⁺
• Genetic Background: involves: 129S4/SvJaeSor * C57BL/6NHsd

hearing/vestibular/ear

increased cochlear inner hair cell number ( J:53290 )

• at P6, heterozygotes display occasional supernumerary inner hair cells throughout the organ of Corti; never observed in wild-type mice

• in contrast, the heterozygous outer hair cell population remains normal relative to wild-type mice

nervous system

increased cochlear inner hair cell number ( J:53290 )

• at P6, heterozygotes display occasional supernumerary inner hair cells throughout the organ of Corti; never observed in wild-type mice

• in contrast, the heterozygous outer hair cell population remains normal relative to wild-type mice

Genotype
MGI:3618584

cn6

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b⁺; Crebbp^tm1Jvd/Crebbp^tm1Jvd; Tg(MMTV-cre)4Mam/0
• Genetic Background: involves: 129 * C57BL/6 * CBA * FVB

neoplasm

increased T cell derived lymphoma incidence ( J:88323 )

• considerably accelerated tumor development

endocrine/exocrine glands

increased T cell derived lymphoma incidence ( J:88323 )

• considerably accelerated tumor development

Genotype
MGI:5468653

cn7

• Allelic Composition: Ccnd3^tm1Pisc/Ccnd3^tm1Pisc; Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Rb1^tm2Brn/Rb1^tm2Brn; Tg(Mx1-cre)1Cgn/0
• Genetic Background: involves: 129S4/SvJaeSor * C57BL/6 * CBA

immune system

immune system phenotype ( J:192031 )

N • mice exhibit normal numbers of thymocytes, double negative cells, double positive cells and pre-T cell proliferation

Genotype
MGI:3044974

cx8

• Allelic Composition: Ccnd1^tm1Dsn/Ccnd1^tm1Dsn; Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
• Genetic Background: involves: 129 * C57BL/6

nervous system

increased pituitary adenoma incidence ( J:66707 )

• double homozygotes showed increased susceptibility to pituitary adenomas arising from the intermediate lobe

mortality/aging

mortality/aging ( J:66707 )

N • double homozygotes did not display premature mortality and developed normally

neoplasm

increased pituitary adenoma incidence ( J:66707 )

• double homozygotes showed increased susceptibility to pituitary adenomas arising from the intermediate lobe

behavior/neurological

abnormal reflex ( J:66707 )

• double homozygotes showed only a moderate "leg-clasping" reflex

craniofacial

craniofacial phenotype ( J:66707 )

N • double mutant mice never displayed misaligned teeth

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:66707 )

N • double homozygotes showed normal lobuloalveolar development of the mammary epithelium

enlarged thymus ( J:66707 )

thymus hyperplasia ( J:66707 )

abnormal corpus luteum morphology ( J:66707 )

♀ • double homozygotes displayed an ovarian defect associated with the inability of cells forming corpus luteum to undergo a timely cell cycle exit

enlarged testis ( J:66707 )

♂

increased pituitary adenoma incidence ( J:66707 )

• double homozygotes showed increased susceptibility to pituitary adenomas arising from the intermediate lobe

growth/size/body

increased body weight ( J:66707 )

• double homozygotes showed an increased body mass, albeit lower than that observed in single Cdkn1b mutant mice

enlarged spleen ( J:66707 )

hematopoietic system

enlarged thymus ( J:66707 )

thymus hyperplasia ( J:66707 )

enlarged spleen ( J:66707 )

immune system

enlarged thymus ( J:66707 )

thymus hyperplasia ( J:66707 )

enlarged spleen ( J:66707 )

reproductive system

abnormal corpus luteum morphology ( J:66707 )

♀ • double homozygotes displayed an ovarian defect associated with the inability of cells forming corpus luteum to undergo a timely cell cycle exit

enlarged testis ( J:66707 )

♂

female infertility ( J:66707 )

♀

vision/eye

disorganized retina layers ( J:66707 )

• despite normal retinal development, double homozygotes displayed focal disorganization of the retinal cytoarchitecture

Genotype
MGI:5449369

cx9

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b⁺; Vsx2^tm1.1Eml/Vsx2^tm1.1Eml
• Genetic Background: involves: 129 * C57BL/6

vision/eye

abnormal eye morphology ( J:190452 )

• substantial improvements in tissue histology and retinal neurogenesis compared to mice homozygous for Vsx2^tm1.1Eml alone

• rescue in the peripheral region is not as strong as in the central region

Genotype
MGI:3842439

cx10

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Rbx1^Gt(XB674)Byg/Rbx1^Gt(XB674)Byg
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJaeSor * C57BL/6J

mortality/aging

embryonic lethality during organogenesis, complete penetrance ( J:147759 )

• die between E9.5 and E10.5

cellular

cellular phenotype ( J:147759 )

N • unlike in Rbx1^Gt(XB674)Byg single homozygous mice, double homozygous embryos show normal cell proliferation at E6.5

Genotype
MGI:3811822

cx11

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b⁺; Myc^tm1Atp/Myc⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJaeSor * FVB/N

growth/size/body

decreased body size ( J:73369 )

• as in Myc^tm1Atp heterozygotes

Genotype
MGI:3811823

cx12

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Myc^tm1Atp/Myc^tm1Atp
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJaeSor * FVB/N

mortality/aging

prenatal lethality, complete penetrance ( J:73369 )

• mice die at mid-gestation

Genotype
MGI:3811821

cx13

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Myc^tm1Atp/Myc⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJaeSor * FVB/N

immune system

decreased T cell proliferation ( J:73369 )

• as in Myc^tm1Atp heterozygotes

growth/size/body

decreased body size ( J:73369 )

• as in Myc^tm1Atp heterozygotes

hematopoietic system

decreased T cell proliferation ( J:73369 )

• as in Myc^tm1Atp heterozygotes

cellular

decreased T cell proliferation ( J:73369 )

• as in Myc^tm1Atp heterozygotes

Genotype
MGI:5544754

cx14

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b⁺; Ptch1^tm1Mps/Ptch1⁺
• Genetic Background: involves: 129S1/Sv * 129S4/SvJaeSor * 129X1/SvJ * C57BL/6

mortality/aging

premature death ( J:205254 )

• median survival of mutants that only develop medulloblastoma is 127 days

neoplasm

increased tumor incidence ( J:205254 )

• 11.8% of mutants develop other tumors, including hemangiosarcomas, intestinal tumors, rhabdomyosarcomas, and lymphomas

increased gastrointestinal tumor incidence ( J:205254 )

increased rhabdomyosarcoma incidence ( J:205254 )

increased lymphoma incidence ( J:205254 )

increased medulloblastoma incidence ( J:205254 )

• 59.7% of mutants develop medulloblastoma

• medulloblastomas are less differentiated and more invasive than medulloblastomas from single Ptch1 heterozygotes, sometimes penetrating the white matter and sometimes obliterating the normal contours of the cerebellar lobes

increased hemangiosarcoma incidence ( J:205254 )

nervous system

increased medulloblastoma incidence ( J:205254 )

• 59.7% of mutants develop medulloblastoma

• medulloblastomas are less differentiated and more invasive than medulloblastomas from single Ptch1 heterozygotes, sometimes penetrating the white matter and sometimes obliterating the normal contours of the cerebellar lobes

hydrocephaly ( J:205254 )

• fraction of mutants develop hydrocephalus unrelated to tumor formation

abnormal cerebellar molecular layer ( J:205254 )

• 1 month old cerebella show preneoplastic lesions in the outer molecular layer where progenitors within the external germinal layer previously resided, suggesting that medulloblastomas arise from granule neuron progenitors

muscle

increased rhabdomyosarcoma incidence ( J:205254 )

digestive/alimentary system

increased gastrointestinal tumor incidence ( J:205254 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
medulloblastoma		DOID:0050902	OMIM:155255	J:205254

Genotype
MGI:5544755

cx15

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Ptch1^tm1Mps/Ptch1⁺
• Genetic Background: involves: 129S1/Sv * 129S4/SvJaeSor * 129X1/SvJ * C57BL/6

mortality/aging

premature death ( J:205254 )

• median survival of mutants that only develop medulloblastoma is 114 days

neoplasm

increased tumor incidence ( J:205254 )

• 30% of mutants develop other tumors, including hemangiosarcomas, intestinal tumors, rhabdomyosarcomas, and lymphomas

• however, no pituitary tumors are seen

increased gastrointestinal tumor incidence ( J:205254 )

increased rhabdomyosarcoma incidence ( J:205254 )

increased lymphoma incidence ( J:205254 )

increased medulloblastoma incidence ( J:205254 )

• 66.7% of mutants develop medulloblastoma

• formation of medulloblastoma formation is accelerated compared to single Ptch1 heterozygotes or double heterozygotes

• medulloblastomas are less differentiated and more invasive than medulloblastomas from single Ptch1 heterozygotes

increased hemangiosarcoma incidence ( J:205254 )

nervous system

increased medulloblastoma incidence ( J:205254 )

• 66.7% of mutants develop medulloblastoma

• formation of medulloblastoma formation is accelerated compared to single Ptch1 heterozygotes or double heterozygotes

• medulloblastomas are less differentiated and more invasive than medulloblastomas from single Ptch1 heterozygotes

hydrocephaly ( J:205254 )

• fraction of mutants develop hydrocephalus unrelated to tumor formation

abnormal cerebellar molecular layer ( J:205254 )

• 1 month old cerebella show preneoplastic lesions in the outer molecular layer where progenitors within the external germinal layer previously resided, suggesting that medulloblastomas arise from granule neuron progenitors

muscle

increased rhabdomyosarcoma incidence ( J:205254 )

digestive/alimentary system

increased gastrointestinal tumor incidence ( J:205254 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
medulloblastoma		DOID:0050902	OMIM:155255	J:205254

Genotype
MGI:4420782

cx16

• Allelic Composition: Cdkn1a^tm1Tyj/Cdkn1a^tm1Tyj; Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJaeSor

digestive/alimentary system

abnormal enterocyte proliferation ( J:111081 )

• following small bowel resection (SBR), mice fail to exhibit an increase in enterocyte proliferation unlike similarly treated wild-type mice

abnormal crypts of Lieberkuhn morphology ( J:111081 )

• following small bowel resection (SBR), mice fail to exhibit an increase in crypt depth unlike similarly treated wild-type mice

abnormal ileum morphology ( J:111081 )

• following small bowel resection (SBR), mice fail to exhibit an increase in ileal weight unlike similarly treated wild-type mice

abnormal small intestinal villus morphology ( J:111081 )

• following small bowel resection (SBR), mice fail to exhibit an increase in villus height unlike similarly treated wild-type mice

homeostasis/metabolism

abnormal response to injury ( J:111081 )

• following small bowel resection (SBR), mice fail to exhibit an increase in ileal weight, villus height, crypt depth, or enterocyte proliferation unlike similarly treated wild-type mice

• however, increase in enterocyte apoptosis following SBR is normal

endocrine/exocrine glands

abnormal crypts of Lieberkuhn morphology ( J:111081 )

• following small bowel resection (SBR), mice fail to exhibit an increase in crypt depth unlike similarly treated wild-type mice

cellular

abnormal enterocyte proliferation ( J:111081 )

• following small bowel resection (SBR), mice fail to exhibit an increase in enterocyte proliferation unlike similarly treated wild-type mice

Genotype
MGI:3624687

cx17

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Tg(KRT5-CDK4)2303Mlrp/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * FVB * SENCAR * SSIN

immune system

enlarged thymus ( J:107588 )

• mutants have increased thymic lymphocyte cellularity

thymus hyperplasia ( J:107588 )

• mutants develop massive thymic hyperplasia; thymuses are 4-fold larger than those of Cdkn1b-null mice and 6-fold larger than Cdk4-deficient mice

hematopoietic system

enlarged thymus ( J:107588 )

• mutants have increased thymic lymphocyte cellularity

thymus hyperplasia ( J:107588 )

• mutants develop massive thymic hyperplasia; thymuses are 4-fold larger than those of Cdkn1b-null mice and 6-fold larger than Cdk4-deficient mice

endocrine/exocrine glands

enlarged thymus ( J:107588 )

• mutants have increased thymic lymphocyte cellularity

thymus hyperplasia ( J:107588 )

• mutants develop massive thymic hyperplasia; thymuses are 4-fold larger than those of Cdkn1b-null mice and 6-fold larger than Cdk4-deficient mice

Genotype
MGI:5468651

cx18

• Allelic Composition: Ccnd3^tm1Pisc/Ccnd3^tm1Pisc; Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
• Genetic Background: involves: 129S4/SvJaeSor

immune system

decreased T cell proliferation ( J:192031 )

• of pre-T cells as in Ccnd3^tm1Pisc homozygotes

thymus hypoplasia ( J:192031 )

• not as severe as in Ccnd3^tm1Pisc homozygotes

decreased double-positive T cell number ( J:192031 )

• as in Ccnd3^tm1Pisc homozygotes

hematopoietic system

decreased T cell proliferation ( J:192031 )

• of pre-T cells as in Ccnd3^tm1Pisc homozygotes

thymus hypoplasia ( J:192031 )

• not as severe as in Ccnd3^tm1Pisc homozygotes

decreased double-positive T cell number ( J:192031 )

• as in Ccnd3^tm1Pisc homozygotes

abnormal bone marrow cell physiology ( J:192031 )

• bone marrow progenitor cells transfected with a retrovirus encoding the constitutively active intracellular domain of Notch1 slightly delays development of T cell acute lymphoblastic leukemia in recipient irradiated wild-type mice from the

endocrine/exocrine glands

thymus hypoplasia ( J:192031 )

• not as severe as in Ccnd3^tm1Pisc homozygotes

cellular

decreased T cell proliferation ( J:192031 )

• of pre-T cells as in Ccnd3^tm1Pisc homozygotes

Genotype
MGI:3037841

cx19

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Trp53^tm1Brd/Trp53^tm1Brd
• Genetic Background: involves: 129S4/SvJaeSor * 129S7/SvEvBrd * C57BL/6J

mortality/aging

decreased tumor-free survival time ( J:87536 )

• the median latency to morbidity from tumor burden is significantly decreased in the double mutant compared to mice homozygous for Trp53^tm1Brd alone

• this effect is synergistic

neoplasm

increased tumor incidence ( J:87536 )

• the most common types of tumors are similar to mice homozygous for Trp53^tm1Brd alone, however additional tumor types are found in the double homozygous mice

increased T cell derived lymphoma incidence ( J:87536 )

• the most common type of tumor is T-cell lymphoma

increased sarcoma incidence ( J:87536 )

• the second most common types of tumor are sarcomas including; rhabdomyosarcoma, osteosarcoma, hemangiosarcoma, and poorly differentiated

endocrine/exocrine glands

increased T cell derived lymphoma incidence ( J:87536 )

• the most common type of tumor is T-cell lymphoma

Genotype
MGI:5581427

cx20

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b⁺; Tg(TG-TPR/NTRK1)#Rstn/0
• Genetic Background: involves: 129S4/SvJaeSor * C3H * C57BL/6 * C57BL/6J

neoplasm

increased thyroid carcinoma incidence ( J:210015 )

• total number of papillary thyroid carcinomas that form is higher than in single Tg(TG-TPR/NTRK1)#Rstn transgenic mice

• however, a delay in onset of papillary thyroid carcinoma is seen compared to mice homozygous for Cdkn1b^tm1Mlf and transgenic for Tg(TG-TPR/NTRK1)#Rstn mice

endocrine/exocrine glands

increased thyroid carcinoma incidence ( J:210015 )

• total number of papillary thyroid carcinomas that form is higher than in single Tg(TG-TPR/NTRK1)#Rstn transgenic mice

• however, a delay in onset of papillary thyroid carcinoma is seen compared to mice homozygous for Cdkn1b^tm1Mlf and transgenic for Tg(TG-TPR/NTRK1)#Rstn mice

Genotype
MGI:5581426

cx21

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Tg(TG-TPR/NTRK1)#Rstn/0
• Genetic Background: involves: 129S4/SvJaeSor * C3H * C57BL/6 * C57BL/6J

neoplasm

increased thyroid carcinoma incidence ( J:210015 )

• mice show a higher incidence of papillary thyroid carcinoma with a shorter latency period and increased proliferation index compared to single transgenic Tg(TG-TPR/NTRK1)#Rstn mice

• total number of papillary thyroid carcinomas is higher than in mice heterozygous for Cdkn1b^tm1Mlf and transgenic for Tg(TG-TPR/NTRK1)#Rstn

• tumor metastases to local cervical lymph nodes, peripheral lymph nodes or lungs are not seen

endocrine/exocrine glands

increased thyroid carcinoma incidence ( J:210015 )

• mice show a higher incidence of papillary thyroid carcinoma with a shorter latency period and increased proliferation index compared to single transgenic Tg(TG-TPR/NTRK1)#Rstn mice

• total number of papillary thyroid carcinomas is higher than in mice heterozygous for Cdkn1b^tm1Mlf and transgenic for Tg(TG-TPR/NTRK1)#Rstn

• tumor metastases to local cervical lymph nodes, peripheral lymph nodes or lungs are not seen

Genotype
MGI:3046061

cx22

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Nkx3-1^tm1.1Saa/Nkx3-1^tm1.1Saa
• Genetic Background: involves: 129S4/SvJaeSor * C57BL/6 * FVB/N

neoplasm

increased prostate intraepithelial neoplasia incidence ( J:89571 )

♂ • incidence of prostatic intraepithelial neoplasia was 100% by 24 weeks of age

preneoplasia ( J:89571 )

• extensive lesions in the prostate

• nuclear crowding and elongation as well as hyperchromasia

• increased proliferation of prostatic epithelial cells

reproductive system

increased prostate intraepithelial neoplasia incidence ( J:89571 )

♂ • incidence of prostatic intraepithelial neoplasia was 100% by 24 weeks of age

endocrine/exocrine glands

increased prostate intraepithelial neoplasia incidence ( J:89571 )

♂ • incidence of prostatic intraepithelial neoplasia was 100% by 24 weeks of age

Genotype
MGI:2653622

cx23

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Tg(MMTV-vHaras)SH1Led/0
• Genetic Background: involves: 129S4/SvJaeSor * C57BL/6J * CD-1

neoplasm

increased tumor growth/size ( J:80271 )

• mice exhibit no effect on the timing or multiplicity of tumor formation, which is largely restricted to mammary and salivary glands, however, once tumors appear, they grow faster than in controls

• the increase in growth rate of induced tumors is particularly striking for salivary tumors

Genotype
MGI:2662503

cx24

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Cdkn2d^tm1Maro/Cdkn2d^tm1Maro
• Genetic Background: involves: 129X1/SvJ * C57BL/6

mortality/aging

postnatal lethality, complete penetrance ( J:58522 )

• double homozygotes die by P18 or shortly thereafter as a result of developing neurologic deficits, indirect metabolic consequences, or both

growth/size/body

decreased body size ( J:58522 )

• at P18, double homozygotes appear consistently smaller than wild-type littermates

weight loss ( J:58522 )

• double homozygotes develop normally until P14 but fail to thrive thereafter

• by P18, double homozygotes weigh significantly less than control littermates

cachexia ( J:58522 )

• double homozygotes appear cachectic prior to death

behavior/neurological

abnormal behavior ( J:58522 )

• as early as P10, all double homozygotes start developing progressive neurological defects, eventually leading to paresis, bradykinesia, tremors, hypertonia, abnormal leg clasping reflexes, light sensitivity, and seizures

impaired righting response ( J:58522 )

• by P18, double homozygotes have trouble righting themselves

limb grasping ( J:58522 )

• when lifted by their tails, double homozygotes hold their limbs by their trunk, whereas wild-type littermates twist, extend their legs, and attempt to find a solid object to grasp, including climbing back up their own tails

tremors ( J:58522 )

bradykinesia ( J:58522 )

paresis ( J:58522 )

seizures ( J:58522 )

• by P18, double homozygotes exhibit seizures

respiratory system

respiratory distress ( J:58522 )

• by P18 or soon thereafter, all double homozygotes exhibit labored (Cheyne-Stokes) respiration

nervous system

nervous system phenotype ( J:58522 )

N • double homozygotes display no gross alterations in brain histology or cytoarchitecture, suggesting that increased neuronal proliferation is balanced by cell death

seizures ( J:58522 )

• by P18, double homozygotes exhibit seizures

increased neuron apoptosis ( J:58522 )

• at P18, double homozygotes show an increased number of pyknotic nuclei and positive apoptotic staining of neurons in layer II of the cortex and in the outer margins of the pyramidal layer of the hippocampus

abnormal neuron morphology ( J:58522 )

• at P18, double homozygotes exhibit increased proliferation of neurons not only in the corpus callosum but in many other parts of the brain, including the hippocampal pyramidal cell layer, layers III and V of the cerebral cortex, and the pontine and brainstem nuclei, all of which are normally quiescent at this age

• in addition, double homozygotes display ectopic neuronal proliferation in the hypothalamus, substantia nigra, and retina

• increased neuronal proliferation observed at P14 is counterbalanced by increased apoptotic cell death at P18

muscle

muscle hypertonia ( J:58522 )

homeostasis/metabolism

dehydration ( J:58522 )

• double homozygotes appear dehydrated prior to death

photosensitivity ( J:58522 )

• by P18, double homozygotes exhibit light sensitivity

cellular

abnormal mitosis ( J:58522 )

• at P18, double homozygotes exhibit ectopic neuronal cell divisions in many brain regions, particularly within the pyramidal layer of the hippocampus

• on the basis of HH3 and NeuN staining, these neurons progress through G2 and M phase and undergo cytokinesis

increased mitotic index ( J:58522 )

• on the basis of histone H3 staining (a marker for late G2 and M-phase progression), these neurons continue to divide after they have migrated to their final positions in the brain

increased neuron apoptosis ( J:58522 )

• at P18, double homozygotes show an increased number of pyknotic nuclei and positive apoptotic staining of neurons in layer II of the cortex and in the outer margins of the pyramidal layer of the hippocampus

increased cell proliferation ( J:58522 )

• metabolic labeling of live animals with BrdU at P14 and P18, combined with immunolabeling of neuronal markers, indicates that subpopulations of CNS differentiated neurons continue to proliferate in all parts of the brain, including normally dormant cells of the hippocampus, cortex, hypothalamus, pons, and brainstem

vision/eye

photosensitivity ( J:58522 )

• by P18, double homozygotes exhibit light sensitivity

Genotype
MGI:3037835

cx25

• Allelic Composition: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf; Trp53^tm1Brd/Trp53^tm1Brd
• Genetic Background: involves: C3H * C57BL/6J * NIH

endocrine/exocrine glands

increased T cell derived lymphoma incidence ( J:87536 )

• the most common type of tumor is T-cell lymphoma

mortality/aging

decreased tumor-free survival time ( J:87536 )

• the median latency to morbidity from tumor burden is significantly decreased in the double mutant compared to mice homozygous for Trp53^tm1Brd alone

• this effect is synergistic

neoplasm

increased tumor incidence ( J:87536 )

• the most common types of tumors are similar to mice homozygous for Trp53^tm1Brd alone, however additional tumor types are found in the double homozygous mice

increased T cell derived lymphoma incidence ( J:87536 )

• the most common type of tumor is T-cell lymphoma

increased sarcoma incidence ( J:87536 )

• the second most common types of tumor are sarcomas including; rhabdomyosarcoma, osteosarcoma, hemangiosarcoma, and poorly differentiated