Phenotypes associated with this allele

• Allele Symbol: Cdkn2d^tm1Maro
• Allele Name: targeted mutation 1, Martine F Roussel
• Allele ID: MGI:1927668
• Summary: 7 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cdkn2d^tm1Maro/Cdkn2d^tm1Maro	involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6 * CD-1	MGI:4420895
hm2	Cdkn2d^tm1Maro/Cdkn2d^tm1Maro	involves: 129P2/OlaHsd * C57BL/6	MGI:2175776
hm3	Cdkn2d^tm1Maro/Cdkn2d^tm1Maro	involves: 129X1/SvJ * C57BL/6	MGI:2662543
hm4	Cdkn2d^tm1Maro/Cdkn2d^tm1Maro	involves: 129X1/SvJ * C57BL/6 * CD-1	MGI:3697505
cx5	Cdkn2c^tm1Bbd/Cdkn2c^tm1Bbd Cdkn2d^tm1Maro/Cdkn2d^tm1Maro	involves: 129P2/OlaHsd * 129S1/Sv * C57BL/6	MGI:2662523
cx6	Cdkn1a^tm1Tyj/Cdkn1a^tm1Tyj Cdkn2d^tm1Maro/Cdkn2d^tm1Maro	involves: 129P2/OlaHsd * 129S2/SvPas * 129X1/SvJ * C57BL/6 * CD-1	MGI:4420894
cx7	Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf Cdkn2d^tm1Maro/Cdkn2d^tm1Maro	involves: 129X1/SvJ * C57BL/6	MGI:2662503

Genotype
MGI:4420895

hm1

• Allelic Composition: Cdkn2d^tm1Maro/Cdkn2d^tm1Maro
• Genetic Background: involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6 * CD-1

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

hearing/vestibular/ear

decreased cochlear inner hair cell number ( J:118337 )

• 29% in the basal and middle region of the cochlea at 2 months

decreased cochlear outer hair cell number ( J:118337 )

• 9% in the basal and middle region of the cochlea at 2 months

nervous system

decreased cochlear inner hair cell number ( J:118337 )

• 29% in the basal and middle region of the cochlea at 2 months

decreased cochlear outer hair cell number ( J:118337 )

• 9% in the basal and middle region of the cochlea at 2 months

Genotype
MGI:2175776

hm2

• Allelic Composition: Cdkn2d^tm1Maro/Cdkn2d^tm1Maro
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

reproductive system

multinucleated giant male germ cells ( J:58959 )

♂ • many giant cells that appear to correspond to apoptotic bodies are observed; these were not seen frequently in wild-type testes sections

increased male germ cell apoptosis ( J:58959 )

♂ • increased apoptosis of germ cells during spermatogenesis

testicular atrophy ( J:58959 )

♂ • testicular atrophy resulting in a 30 to 40% reduction in size relative to wild-type

♂ • however, males remain fertile

abnormal spermatogenesis ( J:58959 )

♂

endocrine/exocrine glands

testicular atrophy ( J:58959 )

♂ • testicular atrophy resulting in a 30 to 40% reduction in size relative to wild-type

♂ • however, males remain fertile

cellular

multinucleated giant male germ cells ( J:58959 )

♂ • many giant cells that appear to correspond to apoptotic bodies are observed; these were not seen frequently in wild-type testes sections

increased male germ cell apoptosis ( J:58959 )

♂ • increased apoptosis of germ cells during spermatogenesis

Genotype
MGI:2662543

hm3

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

reproductive system

abnormal spermatogenesis ( J:68829 )

♂

oligozoospermia ( J:68829 )

♂ • decreased amount of epididymal sperm relative to wild-type

abnormal male meiosis ( J:68829 )

♂ • meiotic delay leading to apoptosis

homeostasis/metabolism

increased circulating follicle stimulating hormone level ( J:68829 )

cellular

oligozoospermia ( J:68829 )

♂ • decreased amount of epididymal sperm relative to wild-type

abnormal male meiosis ( J:68829 )

♂ • meiotic delay leading to apoptosis

abnormal apoptosis ( J:68829 )

Genotype
MGI:3697505

hm4

• Allelic Composition: Cdkn2d^tm1Maro/Cdkn2d^tm1Maro
• Genetic Background: involves: 129X1/SvJ * C57BL/6 * CD-1

hearing/vestibular/ear

cochlear hair cell degeneration ( J:83482 )

• by 2.5 weeks of age, homozygotes display progressive cochlear hair cell loss, with IHCs and the innermost row of OHCs being most affected in the basal to mid-basal cochlear regions

• by 7 weeks, hair cell degeneration affects all rows of hair cells, although IHCs are more severely affected

cochlear inner hair cell degeneration ( J:83482 )

• at 7 weeks, homozygotes exhibit a greater IHC loss (43.3%) relative to all three rows of OHCs (27.8%, 8.1% amd 8.5%, respectively)

cochlear outer hair cell degeneration ( J:83482 )

• at 7 weeks, homozygotes exhibit a less severe OHC loss relative to IHC loss

abnormal cochlear hair cell physiology ( J:83482 )

• at P10, cochlear hair cells are observed to aberrantly re-enter the cell cycle and subsequently undergo apoptosis

increased or absent threshold for auditory brainstem response ( J:83482 )

• between 7 and 15 weeks, homozygotes exhibit a shift in ABR thresholds to ~40 dB SPL

• at 7 months, homozygotes display a continuing increase in ABR thresholds (~50 dB SPL)

absent distortion product otoacoustic emissions ( J:83482 )

• at both 7 and 15 weeks of age, DPOAEs are either absent or abnormally low across the entire test frequency range

nonsyndromic hearing loss ( J:83482 )

sensorineural hearing loss ( J:83482 )

• starting between 7 and 15 weeks of age, homozygotes exhibit progressive hearing loss

nervous system

cochlear hair cell degeneration ( J:83482 )

• by 2.5 weeks of age, homozygotes display progressive cochlear hair cell loss, with IHCs and the innermost row of OHCs being most affected in the basal to mid-basal cochlear regions

• by 7 weeks, hair cell degeneration affects all rows of hair cells, although IHCs are more severely affected

cochlear inner hair cell degeneration ( J:83482 )

• at 7 weeks, homozygotes exhibit a greater IHC loss (43.3%) relative to all three rows of OHCs (27.8%, 8.1% amd 8.5%, respectively)

cochlear outer hair cell degeneration ( J:83482 )

• at 7 weeks, homozygotes exhibit a less severe OHC loss relative to IHC loss

abnormal cochlear hair cell physiology ( J:83482 )

• at P10, cochlear hair cells are observed to aberrantly re-enter the cell cycle and subsequently undergo apoptosis

Genotype
MGI:2662523

cx5

• Allelic Composition: Cdkn2c^tm1Bbd/Cdkn2c^tm1Bbd; Cdkn2d^tm1Maro/Cdkn2d^tm1Maro
• Genetic Background: involves: 129P2/OlaHsd * 129S1/Sv * C57BL/6

neoplasm

increased pheochromocytoma incidence ( J:68829 )

increased pituitary adenoma incidence ( J:68829 )

reproductive system

abnormal germ cell morphology ( J:68829 )

• germ cell apoptosis

decreased germ cell number ( J:68829 )

• germ cell apoptosis

oligozoospermia ( J:68829 )

♂ • 85% decrease in epididymal sperm counts relative to wild-type at 10 and 14 weeks of age

♂ • severely reduced amount of epididymal sperm observed at 6 months of age

asthenozoospermia ( J:68829 )

♂

seminiferous tubule degeneration ( J:68829 )

♂ • atrophic seminiferous tubules

abnormal Leydig cell differentiation ( J:68829 )

♂ • failure to differentiate, not associated with abnormal levels of luteinizing hormone (LH)

increased Leydig cell number ( J:68829 )

♂ • evident at 3 months of age and increased at 6 months

♂ • more severe than leydig hyperplasia observed in Cdkn2c^tm1Bbd

testicular atrophy ( J:68829 )

♂ • atrophy of the testes was more severe than in Cdkn2d^tm1Maro homozygotes

abnormal spermatogenesis ( J:68829 )

♂ • reduced sperm production

abnormal male meiosis ( J:68829 )

♂ • meiotic delay leading to apoptosis

male infertility ( J:68829 )

♂

growth/size/body

increased body weight ( J:68829 )

• increased relative to wild-type and Cdkn2d^tm1Maro homozygous mice

• the weight of females was 92% that of Cdkn2c^tm1Bbd homozygous females

• the weight of males was equal to that of Cdkn2c^tm1Bbd homozygous males

homeostasis/metabolism

decreased circulating testosterone level ( J:68829 )

• 75% reduction in levels relative to wild-type

• associated with a failure of leydig cell differentiation

increased circulating follicle stimulating hormone level ( J:68829 )

endocrine/exocrine glands

seminiferous tubule degeneration ( J:68829 )

♂ • atrophic seminiferous tubules

abnormal Leydig cell differentiation ( J:68829 )

♂ • failure to differentiate, not associated with abnormal levels of luteinizing hormone (LH)

increased Leydig cell number ( J:68829 )

♂ • evident at 3 months of age and increased at 6 months

♂ • more severe than leydig hyperplasia observed in Cdkn2c^tm1Bbd

testicular atrophy ( J:68829 )

♂ • atrophy of the testes was more severe than in Cdkn2d^tm1Maro homozygotes

increased pheochromocytoma incidence ( J:68829 )

increased pituitary adenoma incidence ( J:68829 )

nervous system

increased pituitary adenoma incidence ( J:68829 )

cellular

abnormal germ cell morphology ( J:68829 )

• germ cell apoptosis

decreased germ cell number ( J:68829 )

• germ cell apoptosis

oligozoospermia ( J:68829 )

♂ • 85% decrease in epididymal sperm counts relative to wild-type at 10 and 14 weeks of age

♂ • severely reduced amount of epididymal sperm observed at 6 months of age

abnormal male meiosis ( J:68829 )

♂ • meiotic delay leading to apoptosis

asthenozoospermia ( J:68829 )

♂

Genotype
MGI:4420894

cx6

• Allelic Composition: Cdkn1a^tm1Tyj/Cdkn1a^tm1Tyj; Cdkn2d^tm1Maro/Cdkn2d^tm1Maro
• Genetic Background: involves: 129P2/OlaHsd * 129S2/SvPas * 129X1/SvJ * C57BL/6 * CD-1

hearing/vestibular/ear

decreased cochlear hair cell number ( J:118337 )

• loss of hair cells is more severe than in Cdkn2d^tm1Maro homozygotes

• however, vestibular hair cells are not lost

decreased cochlear outer hair cell number ( J:118337 )

• at P5, mice exhibit a 5% loss of outer hair cells by apoptosis

• at 2 months, mice exhibit a 87% loss of outer hair cells overall, a 62% loss in the basal region, and a 26% loss in the apical region

increased cochlear hair cell number ( J:118337 )

• mice exhibit a transient increase in hair cells

abnormal cochlear inner hair cell morphology ( J:118337 )

• inner nuclear hair cells exhibit abnormal nuclear morphology with a low frequency of polyploidy unlike in wild-type mice

decreased cochlear inner hair cell number ( J:118337 )

• at P5, mice exhibit a 2.5% loss of inner hair cells by apoptosis

• at 2 months, mice exhibit a 66% loss of inner hair cells overall, a 64% loss in the basal region, and a 26% loss in the apical region

abnormal cochlear hair cell physiology ( J:118337 )

• at P3 and P6, auditory hair cells exhibit increased proliferation as measured by S-phase reentry compared to in Cdkn2d^tm1Maro homozyogtes

• proliferation of hair cells increases by P6 but drops off after P10

• increased hair cell proliferation is followed by DNA damage and apoptosis

cellular

polyploidy ( J:118337 )

• inner nuclear hair cells exhibit abnormal nuclear morphology with a low frequency of polyploidy unlike in wild-type mice

nervous system

decreased cochlear hair cell number ( J:118337 )

• loss of hair cells is more severe than in Cdkn2d^tm1Maro homozygotes

• however, vestibular hair cells are not lost

decreased cochlear inner hair cell number ( J:118337 )

• at P5, mice exhibit a 2.5% loss of inner hair cells by apoptosis

• at 2 months, mice exhibit a 66% loss of inner hair cells overall, a 64% loss in the basal region, and a 26% loss in the apical region

decreased cochlear outer hair cell number ( J:118337 )

• at P5, mice exhibit a 5% loss of outer hair cells by apoptosis

• at 2 months, mice exhibit a 87% loss of outer hair cells overall, a 62% loss in the basal region, and a 26% loss in the apical region

increased cochlear hair cell number ( J:118337 )

• mice exhibit a transient increase in hair cells

abnormal cochlear inner hair cell morphology ( J:118337 )

• inner nuclear hair cells exhibit abnormal nuclear morphology with a low frequency of polyploidy unlike in wild-type mice

abnormal cochlear hair cell physiology ( J:118337 )

• at P3 and P6, auditory hair cells exhibit increased proliferation as measured by S-phase reentry compared to in Cdkn2d^tm1Maro homozyogtes

• proliferation of hair cells increases by P6 but drops off after P10

• increased hair cell proliferation is followed by DNA damage and apoptosis

Genotype
MGI:2662503

cx7

• 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