Phenotypes associated with this allele

• Allele Symbol: Cdk4^tm1Bbd
• Allele Name: targeted mutation 1, Mariano Barbacid
• Allele ID: MGI:2154520
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cdk4^tm1Bbd/Cdk4^tm1Bbd	involves: 129S1/Sv * 129X1/SvJ * ICR	MGI:2386959
cx2	Cdk2^tm1Sgo/Cdk2^tm1Sgo Cdk4^tm1Bbd/Cdk4^tm1Bbd Cdk6^tm1Bbd/Cdk6^tm1Bbd	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:3723204
cx3	Cdk4^tm1Bbd/Cdk4^tm1Bbd Cdk6^tm1Bbd/Cdk6^tm1Bbd	involves: 129S1/Sv * 129X1/SvJ * CD-1 * ICR	MGI:3054097

Genotype
MGI:2386959

hm1

• Allelic Composition: Cdk4^tm1Bbd/Cdk4^tm1Bbd
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * ICR

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

mortality/aging

postnatal lethality ( J:54534 )

• slightly lower ratio of homozygotes produced from heterozygote matings (19.6%)

growth/size/body

decreased body size ( J:54534 )

• smaller size noticeable at birth and progressively more noticeable with age

• overall reduction in size of all major organs

decreased body weight ( J:54534 )

• adults were 50% the weight of wild-type and heterozygous controls

cellular

oligozoospermia ( J:54534 )

♂ • severe reduction in spermatozoa in older males

♂ • in males with limited fertility, reduced numbers of spermatids and mature sperm cells were evident

abnormal cell cycle ( J:54534 )

• serum-starved fibroblasts derived from mutant mice exhibited a delay in reaching S phase when placed in a rich environment

homeostasis/metabolism

hyperglycemia ( J:54534 )

• in adult mice

decreased circulating follicle stimulating hormone level ( J:54534 )

• females had low circulating levels of follicle-stimulating hormone

decreased circulating insulin level ( J:54534 )

• adult mice showed hypoinsulinemia

decreased circulating progesterone level ( J:54534 )

• females had low circulating levels of progesterone

increased urine glucose level ( J:54534 )

• high glucose concentrations in urine

ketoaciduria ( J:54534 )

• ketone bodies in urine

reproductive system

oligozoospermia ( J:54534 )

♂ • severe reduction in spermatozoa in older males

♂ • in males with limited fertility, reduced numbers of spermatids and mature sperm cells were evident

abnormal female reproductive system morphology ( J:54534 )

♀

abnormal corpus luteum morphology ( J:54534 )

♀ • defect in corpus luteum formation

small ovary ( J:54534 )

♀

abnormal male reproductive system morphology ( J:54534 )

♂

abnormal seminiferous tubule morphology ( J:54534 )

♂ • degeneration of primary spermatocytes

abnormal Sertoli cell morphology ( J:54534 )

♂ • vacuolized Sertoli-cell cytoplasm

decreased Leydig cell number ( J:54534 )

♂ • reduced numbers of Leydig cells with numerous apoptotic bodies

decreased testis weight ( J:54534 )

♂ • 75% reduction in size and weight of testes compared to controls

abnormal female reproductive system physiology ( J:54534 )

♀

delayed estrus ( J:54534 )

♀ • moderate delay in passing through estrus

female infertility ( J:54534 )

♀ • infertile, failed to reproduce with wild-type males

abnormal male reproductive system physiology ( J:54534 )

♂

reduced male fertility ( J:54534 )

♂ • most sterile, 80% failed to induce pregnancy

♂ • males that did produce offspring had small litters (3 - 6 pups) and reproduced only for a short period (2 - 3 months of age)

behavior/neurological

polydipsia ( J:54534 )

abnormal locomotor behavior ( J:54534 )

• impaired locomotion

impaired limb coordination ( J:54534 )

• staggering

hyperactivity ( J:54534 )

renal/urinary system

increased urine glucose level ( J:54534 )

• high glucose concentrations in urine

ketoaciduria ( J:54534 )

• ketone bodies in urine

polyuria ( J:54534 )

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:54534 )

• mice 2 months of age or older showed severe deformity and reduction in the size of the islets of the pancreas

small pancreatic islets ( J:54534 )

abnormal corpus luteum morphology ( J:54534 )

♀ • defect in corpus luteum formation

small ovary ( J:54534 )

♀

abnormal seminiferous tubule morphology ( J:54534 )

♂ • degeneration of primary spermatocytes

abnormal Sertoli cell morphology ( J:54534 )

♂ • vacuolized Sertoli-cell cytoplasm

decreased Leydig cell number ( J:54534 )

♂ • reduced numbers of Leydig cells with numerous apoptotic bodies

decreased testis weight ( J:54534 )

♂ • 75% reduction in size and weight of testes compared to controls

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 1 diabetes mellitus		DOID:9744	OMIM:222100	J:54534

Genotype
MGI:3723204

cx2

• Allelic Composition: Cdk2^tm1Sgo/Cdk2^tm1Sgo; Cdk4^tm1Bbd/Cdk4^tm1Bbd; Cdk6^tm1Bbd/Cdk6^tm1Bbd
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

mortality/aging

lethality throughout fetal growth and development, complete penetrance ( J:124678 )

• mice begin to die around E13.5 and all are dying by E15.5

embryonic lethality during organogenesis, incomplete penetrance ( J:124678 )

• mice begin to die around E13.5 and all are dying by E15.5

growth/size/body

decreased embryo size ( J:124678 )

• between E12.5 and E13.5, embryos are 25% to 40% smaller than wild-type mice

cardiovascular system

decreased myocardial fiber number ( J:124678 )

• the number of proliferating cardiomyocytes is decreased resulting in thin ventricular walls

thin ventricular wall ( J:124678 )

• ventricular walls are thinner than in wild-type mice due to a decrease in the number of proliferating cardiomyocytes

cellular

decreased cell proliferation ( J:124678 )

• proliferation of mouse embryonic fibroblast cells is partially compromised

• exiting quiescence following serum treatment is delayed

liver/biliary system

liver hypoplasia ( J:124678 )

• between E12.5 and E13.5, livers exhibit a three-fold reduction in cellularity that is not accounted for by the decrease in embryo size

hematopoietic system

abnormal common myeloid progenitor cell morphology ( J:124678 )

• common myeloid progenitor cells are reduced 8-fold in number

muscle

decreased myocardial fiber number ( J:124678 )

• the number of proliferating cardiomyocytes is decreased resulting in thin ventricular walls

embryo

decreased embryo size ( J:124678 )

• between E12.5 and E13.5, embryos are 25% to 40% smaller than wild-type mice

Genotype
MGI:3054097

cx3

• Allelic Composition: Cdk4^tm1Bbd/Cdk4^tm1Bbd; Cdk6^tm1Bbd/Cdk6^tm1Bbd
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * CD-1 * ICR

mortality/aging

lethality throughout fetal growth and development, incomplete penetrance ( J:92529 )

• 25% of homozygotes are dead by E14.5

• 50% dead by E18.5

neonatal lethality, complete penetrance ( J:92529 )

• of the few homozygotes to be born alive, all were dead within a few hours of birth

embryo

decreased embryo size ( J:92529 )

• embryos well formed but small

growth/size/body

decreased embryo size ( J:92529 )

• embryos well formed but small

hematopoietic system

extramedullary hematopoiesis ( J:92529 )

• decreased numbers of erythroid precursors in the liver and few in proliferative stage

• lymphoid and myeloid lineage reductions are disproportionate

• proliferative potential of all stem cells is severely reduced

abnormal erythrocyte morphology ( J:92529 )

• RBCs are megaloblastic in appearance

decreased erythrocyte cell number ( J:92529 )

• decreased peripheral RBC counts

decreased hematopoietic stem cell number ( J:92529 )

• hematopoietic stem cell numbers reduced in proportion to reduced cellularity

liver/biliary system

liver hypoplasia ( J:92529 )

• small livers with significantly reduced cellularity by E15.5