Phenotypes associated with this allele

• Allele Symbol: Bmal1^tm1Bra
• Allele Name: targeted mutation 1, Christopher A Bradfield
• Allele ID: MGI:2180361
• Summary: 11 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Bmal1^tm1Bra/Bmal1^tm1Bra	B6.129-Bmal1^tm1Bra	MGI:3714770
hm2	Bmal1^tm1Bra/Bmal1^tm1Bra	involves: 129	MGI:2655516
hm3	Bmal1^tm1Bra/Bmal1^tm1Bra	involves: 129/Sv * C57BL/6	MGI:4362032
hm4	Bmal1^tm1Bra/Bmal1^tm1Bra	involves: 129/Sv * C57BL/6 * C57BL/6J	MGI:4366727
ht5	Bmal1^tm1Bra/Bmal1^+	involves: 129 * C57BL/6	MGI:5302034
cn6	Bmal1^tm1Bra/Bmal1^tm1Weit Syt10^tm1.1(icre)Geno/Syt10^+	involves: 129S2/SvPas * 129S4/SvJaeSor * C57BL/6	MGI:5297480
cn7	Bmal1^tm1Bra/Bmal1^tm1Weit Syt10^tm1.1(icre)Geno/Syt10^tm1.1(icre)Geno	involves: 129S2/SvPas * 129S4/SvJaeSor * C57BL/6	MGI:5297485
cx8	Bmal1^tm1Bra/Bmal1^+ Usp2^tm1.1Bjc/Usp2^+	involves: 129 * C57BL/6	MGI:5302035
cx9	Bmal1^tm1Bra/Bmal1^tm1Bra Syt10^tm1.1(icre)Geno/Syt10^tm1.1(icre)Geno	involves: 129S2/SvPas * 129S4/SvJaeSor * C57BL/6	MGI:5297481
cx10	Bmal1^tm1Bra/Bmal1^tm1Bra Tg(Scg2-tTA)1Jt/0 Tg(tetO-Arntl)1Jt/0	involves: 129/Sv * C57BL/6J * CD-1	MGI:3714773
cx11	Bmal1^tm1Bra/Bmal1^tm1Bra Tg(ACTA1-Arntl)1Jt/0	involves: 129/Sv * C57BL/6J * CD-1	MGI:3714769

Genotype
MGI:3714770

hm1

• Allelic Composition: Bmal1^tm1Bra/Bmal1^tm1Bra
• Genetic Background: B6.129-Bmal1^tm1Bra

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

Joint abnormalities with ectopic ossification in Bmal1^tm1Bra/Bmal1^tm1Bra mice

limbs/digits/tail

abnormal knee joint morphology ( J:97108 )

• in the knee by 26 weeks of age increased proliferation is seen in the synovial fibroblasts

mortality/aging

premature death ( J:110697 , J:116189 )

• most die between 26 and 52 weeks of age (J:110697)

• average lifespan is 37 +/- 12 weeks (J:110697)

• maximum lifespan is 72 weeks of age (J:110697)

• 29% of animals do not survive for 10 months (J:116189)

premature aging ( J:110697 , J:191844 )

• display age related sarcopenia and osteoporosis at 40 weeks of age (J:110697)

• mice display a number of age related phenotypes at an earlier age compared to wild-type controls (J:110697)

♂ • mice exhibit age-induced circulatory changes showing accelerated thrombogenicity at an earlier age than wild-type mice (J:191844)

behavior/neurological

impaired righting response ( J:97108 )

• seen in mice over 20 weeks of age

• hindquarters appear more affected than forequarters

abnormal posture ( J:97108 )

• seen in mice over 20 weeks of age

abnormal tail movements ( J:97108 )

• stiff tail after 20 weeks of age

abnormal gait ( J:97108 )

• seen in mice over 20 weeks of age

abnormal circadian behavior ( J:125921 )

• diurnal variation in activity is abolished

• however, ultradian rhythms are maintained and are stronger than any residual circadian rhythms

growth/size/body

decreased body size ( J:110697 )

• by 52 weeks of age mice are about half the size of wild-type controls

decreased body weight ( J:97108 , J:116189 )

• by 26 weeks of age mice weigh 23% less than controls (J:97108)

• low body weigh relative to wild-type (J:116189)

weight loss ( J:97108 , J:110697 )

• progressive weight loss starting after 20 weeks of age (J:97108)

• growth is similar to controls until about 15 weeks of age (J:97108)

• by 20 weeks of age mice are losing about 0.4g/week (J:97108)

• starting between 16 to 26 weeks of age (J:110697)

postnatal growth retardation ( J:110697 )

• starting around 16 - 18 weeks of age

skeleton

skeleton phenotype ( J:97108 )

N • despite extensive ectopic calcification, bone mineral density is not significantly different from heterozygous controls

abnormal knee joint morphology ( J:97108 )

• in the knee by 26 weeks of age increased proliferation is seen in the synovial fibroblasts

calcified tendon ( J:97108 )

• by 11 weeks of age calcification of the calcaneal tendon is seen

• by 26 weeks of age extensive calcification of the calcaneal tendon is seen

• by 36 weeks of age chondrification and calcification is seen in the lateral collateral ligament and cruciate ligaments

• calcification/ossification appears to be limited to tendons closely associated with bone insertion sites in the appendicular and axial skeleton

calcified calcaneal tendon ( J:97108 , J:116189 )

• at 11 weeks of age calcification of the calcaneal tendon is seen (J:97108)

• by 26 weeks of age extensive calcification of the calcaneal tendon is seen (J:97108)

• significant calcaneal tendon calcification (J:116189)

abnormal thoracic cage morphology ( J:97108 )

• progressive calcification is seen in areas around bone cartilage junctions in the rib cage with calcified nodules seen at costal chondral and costal sternal junctions

• costal sternal junctions show proliferative bony bridging from the costal cartilage to the sternum

• however, muscle fiber attachment appears normal

abnormal costal cartilage morphology ( J:97108 )

• costal sternal junctions show proliferative bony bridging from the costal cartilage to the sternum

• costal cartilage shows increased matrix deposition and bone proliferation

abnormal rib morphology ( J:97108 )

• by 40 weeks of age calcification around bone cartilage junctions results in a severe distortion of the anatomy of the ribs

abnormal vertebral column morphology ( J:97108 )

• at 35 weeks of age evidence of spinal compression is seen

calcified intervertebral disk ( J:97108 )

• at 26 weeks of age calcification is seen in the sacral and thoracic regions but not in the lumbar region

osteoporosis ( J:110697 )

• at 40 weeks of age

calcified joint ( J:97108 )

• at 6 and 8 weeks of age small areas of calcification extending from the insertion of the calcaneal tendon are seen in the tarsocrural joint

• by 11 weeks of age, calcified nodules are often seen on the lateral side of the tarsal joint

• by 26 weeks of age, calcified bridging is seen between tarsal bones

• progressive calcification is seen in areas around bone cartilage junctions in the rib cage with calcified nodules seen at costal chondral and costal sternal junctions

• prominent calcified areas extend from the patella as well as along the medial collateral ligament

fused joints ( J:97108 )

• by 26 weeks of age, calcified bridging is seen between tarsal bones

• by 35 weeks of age, severe bony ankylosis is seen obscuring the normal anatomy of the tarsocrural joint

thoracic vertebral fusion ( J:97108 )

• at 35 weeks of age bridging ankylosis is seen on both the dorsal and ventral aspects of the intervertebral joints throughout the thoracic spine

sacral vertebral fusion ( J:97108 )

• large osteophytes bridge the sacral vertebrae and complete fusion is seen between S2 and S3 at 35 weeks of age

abnormal ligament morphology ( J:97108 )

• by 26 weeks of age calcification of the medial collateral ligament is seen

• by 36 weeks of age chondrification and calcification is seen in the lateral collateral ligament and cruciate ligaments

• calcification/ossification appears to be limited to ligaments closely associated with bone insertion sites in the appendicular and axial skeleton

ectopic bone ( J:97108 )

• by 40 weeks of age ectopic ossification is seen in nearly every joint

• at 26 weeks of age moderate osteophyte formation is seen at the junction of vertebral bodies in the sacral and thoracic regions

• at 35 weeks of age osteophyte formation is seen at the junction of vertebral bodies in the lumbar region

homeostasis/metabolism

abnormal circulating adrenaline level ( J:125921 )

• the diurnal variation in restraint induced changes in adrenaline level is abolished

decreased circulating adrenaline level ( J:125921 )

• at both ZT2 and ZT14

decreased circulating noradrenaline level ( J:125921 )

• at both Zeitgeber time (ZT) 2 and ZT14

increased circulating osteocalcin level ( J:97108 )

• levels of osteocalcin are increased

abnormal circulating protein level ( J:191844 )

♂ • increase in the percentage of plasma factor VII at 30 weeks of age

increased circulating factor VIII level ( J:191844 )

♂ • increase in the percentage of plasma factor VIII at 10, but not 30, weeks of age

increased circulating fibrinogen level ( J:191844 )

♂ • increase in the level of plasma fibrinogen at 10 and 30 weeks of age

increased partial thromboplastin time ( J:191844 )

• prolongation of the activated partial thrombosplastin time

decreased prothrombin time ( J:191844 )

• shortening of the prothrombin time by 1.6 seconds in 10 week old mice and 0.8 seconds in 30 week old mice

increased susceptibility to induced thrombosis ( J:191844 )

♂ • in vascular injury-induced thrombosis, 10 week old mutants show shortened arteriolar and venular occlusion times, indicating early thrombogenicity

abnormal venous thrombosis ( J:191844 )

♂ • numerous thrombi are seen in the venous sinus of penile sections from older males with priapism; thrombi contain platelets and fibrin and fibrin-rich laminar thrombus formation is seen extensively lining the endothelium

hypercoagulability ( J:191844 )

♂ • prolongation of the activated partial thrombosplastin time and a shortening of the prothrombin time by 1.6 seconds in 10 week old mice and 0.8 seconds in 30 week old mice, as well as increased plasma fibrinogen, factor VII and VIII levels indicate a hypercoagulable state that increases with age

dehydration ( J:97108 )

• after 20 weeks of age appear progressively dehydrated

abnormal nitric oxide homeostasis ( J:191844 )

♂ • basal nitric oxide release is attenuated in the thoracic aorta at 30 weeks of age

abnormal metabolism ( J:110697 )

• at ZT10 in 40 week old mice, the accumulation of reactive oxygen species is increased in the kidney, heart and spleen but decreased in the liver relative to time and age matched controls

• increase in reactive oxygen species accumulation is age and tissue dependent

reproductive system

small seminal vesicle ( J:110697 )

♂ • detectable by 10 weeks of age and becoming more pronounced with age

decreased testis weight ( J:110697 )

♂ • at 40 weeks of age

priapism ( J:191844 )

♂ • mutants develop spontaneous priapism that increases with age, from 0% at 10 weeks to 8% at 20-25 weeks, and 60% at 25-30 weeks, which is not seen in wild-type mice at any age

♂ • numerous thrombi are seen in the venous sinus of penile sections; thrombi contain platelets and fibrin and fibrin-rich laminar thrombus formation is seen extensively lining the endothelium

infertility ( J:110697 )

adipose tissue

decreased subcutaneous adipose tissue amount ( J:110697 )

• at 40 weeks of age but not at 10 weeks of age

decreased abdominal adipose tissue amount ( J:110697 )

• at 40 weeks of age

decreased total body fat amount ( J:110697 )

• at 40 weeks of age

hematopoietic system

hematopoietic system phenotype ( J:110697 )

N • at 10 and 40 weeks of age no differences are detected in the numbers of red blood cells or platelets

impaired leukocyte tethering or rolling ( J:191844 )

♂ • despite an increase in leukocytes, lower numbers of rolling leukocytes over endothelium when activated with A23187 are seen in mutants compared to wild-type at both 10 and 30 weeks of age

increased megakaryocyte cell number ( J:191844 )

♂ • density of von Willebrand Factor-positive megakaryocytes in 30 week old bone marrow is higher than in controls

thrombocytosis ( J:191844 )

♂ • increase in platelet count at 30 weeks of age

♂ • despite high platelet numbers at 30 weeks of age, platelet aggregation assays show a normal platelet response to the agonist ADP

decreased leukocyte cell number ( J:110697 )

• decrease in the number of white blood cells at 40 weeks of age compared to age matched controls

decreased basophil cell number ( J:191844 )

♂ • decrease in basophils at 30 weeks of age

decreased lymphocyte cell number ( J:110697 )

• the total number and percentage of lymphocytes are decreased at 40 weeks of age

increased leukocyte cell number ( J:191844 )

♂ • increase in white blood cell count at 10, but not 30, weeks of age

increased eosinophil cell number ( J:191844 )

♂ • increase in eosinophils at 10, but not 30, weeks of age

increased neutrophil cell number ( J:110697 , J:191844 )

• the total number and percentage of neutrophils are increased at 40 weeks of age (J:110697)

♂ • neutrophil numbers are increased 2-fold at 10 weeks of age and 1.2-fold at 30 weeks of age (J:191844)

increased lymphocyte cell number ( J:191844 )

♂ • increase in lymphocytes at 10, but not 30, weeks of age

increased monocyte cell number ( J:110697 )

• the total number and percentage of monocytes are increased at 40 weeks of age

decreased spleen weight ( J:110697 )

• at 30 and 40 weeks of age

cardiovascular system

vascular smooth muscle hyperplasia ( J:191844 )

♂ • smooth muscle cell density is higher in aorta segments at 10, but not 30, weeks of age

decreased heart weight ( J:110697 )

• at 40 weeks of age

abnormal circadian regulation of systemic arterial blood pressure ( J:125921 )

• diurnal variation in mean arterial pressure is abolished

• however, ultradian rhythms are maintained and are stronger than any residual circadian rhythms

• the diurnal variation in restraint induced changes in blood pressure is abolished and the stress induced alteration in blood pressure is lower at ZT12

abnormal circadian regulation of heart rate ( J:125921 )

• diurnal variation in heart rate is abolished

decreased heart rate ( J:125921 )

• only during the active phase

decreased mean systemic arterial blood pressure ( J:125921 )

• expected elevation during the dark phase is absent

• decreased in both the light and dark phases compared to wild-type controls

hypotension ( J:125921 )

abnormal vascular smooth muscle physiology ( J:191844 )

♂ • endothelium-dependent vasomotor responses are altered, with an increase of phenylephrine contraction induced by NOS inhibitors and suppression of acetylcholine-muscarinic receptor-induced endothelium-dependent relaxations in aortic rings of mutants, particularly at 30 weeks of age

♂ • however, mutants exhibit normal contractility of aortic smooth muscle cells as indicated by normal contractile responses to the alpha1-adrenoreceptor agonist phenylephrine when eNOS activity is blocked and normal responsiveness to exogenous nitric oxide released by the nitric oxide donor diethylamine NONOate

increased vasoconstriction ( J:191844 )

♂ • smooth muscle cells show an increase of phenylephrine evoked contraction induced by NOS inhibitors in aortic rings of mutants, particularly at 30 weeks of age

decreased vasodilation ( J:191844 )

♂ • smooth muscle cells exhibit suppression of acetylcholine-muscarinic receptor-induced endothelium-dependent relaxations in aortic rings of mutants, particularly at 30 weeks of age

cornea vascularization ( J:110697 )

• corneal inflammation begins as massive neovascularization

vision/eye

increased incidence of corneal inflammation ( J:110697 )

• at 40 weeks of age over 50% of mice display progressive corneal inflammation

• corneal inflammation begins as massive neovascularization, lymphoid cell infiltration and ulceration of the outer layer of the cornea

abnormal cornea morphology ( J:110697 )

• corneal inflammation begins as ulceration of the outer layer of the cornea

• keratin deposits are seen

cornea vascularization ( J:110697 )

• corneal inflammation begins as massive neovascularization

cornea epithelium hyperplasia ( J:110697 )

• hyperplastic

abnormal cornea stroma morphology ( J:110697 )

• ulceration disrupts the stromal structure

abnormal lens morphology ( J:110697 )

• the lens posterior zone contains enlarged infiltrating epithelial cells

abnormal lens fiber morphology ( J:110697 )

• the density of cortical and nucleus fibers is increased

cataract ( J:110697 )

• by 30 weeks of age all mice have various grades of cataracts in one or both eyes

muscle

vascular smooth muscle hyperplasia ( J:191844 )

♂ • smooth muscle cell density is higher in aorta segments at 10, but not 30, weeks of age

abnormal vascular smooth muscle physiology ( J:191844 )

♂ • endothelium-dependent vasomotor responses are altered, with an increase of phenylephrine contraction induced by NOS inhibitors and suppression of acetylcholine-muscarinic receptor-induced endothelium-dependent relaxations in aortic rings of mutants, particularly at 30 weeks of age

♂ • however, mutants exhibit normal contractility of aortic smooth muscle cells as indicated by normal contractile responses to the alpha1-adrenoreceptor agonist phenylephrine when eNOS activity is blocked and normal responsiveness to exogenous nitric oxide released by the nitric oxide donor diethylamine NONOate

increased vasoconstriction ( J:191844 )

♂ • smooth muscle cells show an increase of phenylephrine evoked contraction induced by NOS inhibitors in aortic rings of mutants, particularly at 30 weeks of age

decreased vasodilation ( J:191844 )

♂ • smooth muscle cells exhibit suppression of acetylcholine-muscarinic receptor-induced endothelium-dependent relaxations in aortic rings of mutants, particularly at 30 weeks of age

decreased muscle weight ( J:110697 )

• at 40 weeks of age

calcified tendon ( J:97108 )

• by 11 weeks of age calcification of the calcaneal tendon is seen

• by 26 weeks of age extensive calcification of the calcaneal tendon is seen

• by 36 weeks of age chondrification and calcification is seen in the lateral collateral ligament and cruciate ligaments

• calcification/ossification appears to be limited to tendons closely associated with bone insertion sites in the appendicular and axial skeleton

calcified calcaneal tendon ( J:97108 , J:116189 )

• at 11 weeks of age calcification of the calcaneal tendon is seen (J:97108)

• by 26 weeks of age extensive calcification of the calcaneal tendon is seen (J:97108)

• significant calcaneal tendon calcification (J:116189)

renal/urinary system

decreased kidney weight ( J:110697 )

• at 40 weeks of age

respiratory system

decreased lung weight ( J:110697 )

• at 40 weeks of age

immune system

impaired leukocyte tethering or rolling ( J:191844 )

♂ • despite an increase in leukocytes, lower numbers of rolling leukocytes over endothelium when activated with A23187 are seen in mutants compared to wild-type at both 10 and 30 weeks of age

decreased leukocyte cell number ( J:110697 )

• decrease in the number of white blood cells at 40 weeks of age compared to age matched controls

decreased basophil cell number ( J:191844 )

♂ • decrease in basophils at 30 weeks of age

decreased lymphocyte cell number ( J:110697 )

• the total number and percentage of lymphocytes are decreased at 40 weeks of age

increased leukocyte cell number ( J:191844 )

♂ • increase in white blood cell count at 10, but not 30, weeks of age

increased eosinophil cell number ( J:191844 )

♂ • increase in eosinophils at 10, but not 30, weeks of age

increased neutrophil cell number ( J:110697 , J:191844 )

• the total number and percentage of neutrophils are increased at 40 weeks of age (J:110697)

♂ • neutrophil numbers are increased 2-fold at 10 weeks of age and 1.2-fold at 30 weeks of age (J:191844)

increased lymphocyte cell number ( J:191844 )

♂ • increase in lymphocytes at 10, but not 30, weeks of age

increased monocyte cell number ( J:110697 )

• the total number and percentage of monocytes are increased at 40 weeks of age

decreased spleen weight ( J:110697 )

• at 30 and 40 weeks of age

increased circulating fibrinogen level ( J:191844 )

♂ • increase in the level of plasma fibrinogen at 10 and 30 weeks of age

increased incidence of corneal inflammation ( J:110697 )

• at 40 weeks of age over 50% of mice display progressive corneal inflammation

• corneal inflammation begins as massive neovascularization, lymphoid cell infiltration and ulceration of the outer layer of the cornea

endocrine/exocrine glands

small seminal vesicle ( J:110697 )

♂ • detectable by 10 weeks of age and becoming more pronounced with age

decreased testis weight ( J:110697 )

♂ • at 40 weeks of age

integument

decreased subcutaneous adipose tissue amount ( J:110697 )

• at 40 weeks of age but not at 10 weeks of age

retarded hair growth ( J:110697 )

• at 30 weeks of age hair regrowth after shaving is delayed with only 1 of 5 mice showing partial regrowth after 3 months

• however, at 10 weeks of age hair regrowth is normal

cellular

impaired leukocyte tethering or rolling ( J:191844 )

♂ • despite an increase in leukocytes, lower numbers of rolling leukocytes over endothelium when activated with A23187 are seen in mutants compared to wild-type at both 10 and 30 weeks of age

Genotype
MGI:2655516

hm2

• Allelic Composition: Bmal1^tm1Bra/Bmal1^tm1Bra
• Genetic Background: involves: 129

reproductive system

decreased uterus weight ( J:115188 )

♀

prolonged estrous cycle ( J:151819 )

♀ • cycle length is 49% longer

♀ • however, the proportion of time spent in each stage is not different from controls

failure of embryo implantation ( J:151819 )

♀ • in the absence of progesterone treatment no implantation sites are seen

♀ • treatment with progesterone beginning at gestational day 3.5 partially rescues the implantation defect

female infertility ( J:151819 )

♀

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:151819 )

N • no difference is detected in estradiol levels during gestation

decreased circulating progesterone level ( J:151819 )

• levels are lower compared to controls regardless of the time of day on day 3 to day 4 of gestation

abnormal circulating protein level ( J:155089 )

• at zeitgeber time (ZT) 14, mice exhibit decreased plasminogen activator inhibitor-1 (PAI-1) levels compared with wild-type mice

abnormal glucose homeostasis ( J:131694 )

• diurnal variation in glucose levels is disrupted

impaired gluconeogenesis ( J:131694 )

increased insulin sensitivity ( J:131694 )

• profound hypoglycemic response regardless of the time of day

abnormal lipid homeostasis ( J:131694 )

• diurnal variation in triglyceride levels is disrupted

abnormal response to injury ( J:155089 )

• time to thrombotic vascular occlusion (TTVO) subsequent to photochemical injury is shorter than in similarly treated wild-type mice

impaired wound healing ( J:193286 )

• show severe wound healing defects characterized by lack of epithelial coverage and a highly disorganized granulation tissue

• most wounds consist mainly of an inflammatory fibrin clot with hardly any fibroblast or keratinocyte proliferation

behavior/neurological

abnormal locomotor activation ( J:66502 )

• level of wheel-running activity in mutants is >3-fold lower during a light cycle and in constant darkness relative to wild-type mice

arrhythmic circadian behavior persistence ( J:66502 )

• when placed in constant darkness after entrainment to a 12 hour/12 hour light/dark schedule, homozygotes do not express any circadian rhythm or locomotor activity in constant darkness

abnormal circadian behavior phase ( J:66502 )

• when a 6 hour light pulse is administered 22 days after placement in constant darkness, no effect on locomotor behavior in null mice is observed nor are there phase shifts or suppression of activity, whereas wild-type mice show a ~3.5 hour phase delay after a light pulse

• few null mutants begin activity within 0.5 hours of lights-off, and 2/17 do not become active at all, whereas all wild-type and heterozygous mice begin activity within 0.5 hours

• 28% of wheel-running activity of mutants is during the light phase, in contrast to 4.2 or 4.1% during light phase in wild-type or heterozygous mice

vision/eye

vision/eye phenotype ( J:124157 )

N • retinas are indistinguishable in morphology or cellular organization from wild-type littermates

abnormal eye electrophysiology ( J:124157 )

• under dark-adapted conditions, ERG b-wave is abnormal with 30% reduced amplitude relative to wild-type mice; ratio of b-wave to a-wave amplitude is highly significant

• under light-adapted conditions, ERG b-wave amplitude is reduced by 60%

adipose tissue

increased total fat pad weight ( J:115188 )

skeleton

skeleton phenotype ( J:115188 )

N • despite the increase in osteoblast number no increase in bone mass is detected

increased osteoblast cell number ( J:115188 )

increased bone resorption ( J:115188 )

• at 2 months of age

Genotype
MGI:4362032

hm3

• Allelic Composition: Bmal1^tm1Bra/Bmal1^tm1Bra
• Genetic Background: involves: 129/Sv * C57BL/6

mortality/aging

premature death ( J:135933 )

• survival time of about 6 months

behavior/neurological

abnormal sleep pattern ( J:135933 )

• display increases in total sleep, sleep fragmentation, and EEG delta power under baseline conditions

• display attenuated compensatory response following acute sleep deprivation

abnormal circadian sleep/wake cycle ( J:135933 )

• attenuated rhythm of sleep and wakefulness distribution across the 24 h period

fragmentation of sleep/wake states ( J:135933 )

homeostasis/metabolism

decreased insulin secretion ( J:162641 )

• islets show up to a 60% reduction in insulin secretion in response to glucose, KCI, exendin 4, forskolin and 8-bromo-cAMP

increased blood urea nitrogen level ( J:135933 )

• at 4 months of age

decreased circulating glucose level ( J:135933 )

• at 4 months of age

increased circulating alanine transaminase level ( J:135933 )

• at 4 months of age

increased circulating aspartate transaminase level ( J:135933 )

• at 4 months of age

decreased plasma anion gap ( J:135933 )

• at 4 months of age

hematopoietic system

abnormal B cell differentiation ( J:118522 )

• partial block in the transition from immature B220^low to mature B220^high cells

• transfer of null cells into wild-type mice rescues B cell development and wild-type cells transferred into null mice show a partial block in development suggesting an alteration in the bone marrow microenvironment

increased neutrophil cell number ( J:135933 )

• increase in segmented neutrophil levels at 4 - 5 months of age

thrombocytosis ( J:135933 )

• at 4 - 5 months of age

abnormal T cell subpopulation ratio ( J:118522 )

• the percentage of CD4+ T cells is slightly increased in the blood and spleen

• however, the total number of CD4+ cells is not changed

decreased lymphocyte cell number ( J:118522 , J:135933 )

• decrease in the number of lymphocytes and white blood cells in the peripheral blood (J:118522)

• decrease in the number of lymphocytes and white blood cells in the peripheral blood at 4 - 5 months of age (J:135933)

decreased B cell number ( J:118522 , J:135933 )

• in the peripheral blood and spleen (J:118522)

• the numbers of B220+ IgM+, CD23+ B220+, and B220+ I-A^b+ cells are decreased in the spleen (J:118522)

decreased transitional stage B cell number ( J:118522 )

• decrease in the numbers of type I and type II transitional B cells in the spleen

decreased follicular B cell number ( J:118522 )

decreased IgG1 level ( J:118522 )

• following exposure to human peripheral blood lymphocytes

immune system

abnormal B cell differentiation ( J:118522 )

• partial block in the transition from immature B220^low to mature B220^high cells

• transfer of null cells into wild-type mice rescues B cell development and wild-type cells transferred into null mice show a partial block in development suggesting an alteration in the bone marrow microenvironment

increased neutrophil cell number ( J:135933 )

• increase in segmented neutrophil levels at 4 - 5 months of age

abnormal T cell subpopulation ratio ( J:118522 )

• the percentage of CD4+ T cells is slightly increased in the blood and spleen

• however, the total number of CD4+ cells is not changed

decreased lymphocyte cell number ( J:118522 , J:135933 )

• decrease in the number of lymphocytes and white blood cells in the peripheral blood (J:118522)

• decrease in the number of lymphocytes and white blood cells in the peripheral blood at 4 - 5 months of age (J:135933)

decreased B cell number ( J:118522 , J:135933 )

• in the peripheral blood and spleen (J:118522)

• the numbers of B220+ IgM+, CD23+ B220+, and B220+ I-A^b+ cells are decreased in the spleen (J:118522)

decreased transitional stage B cell number ( J:118522 )

• decrease in the numbers of type I and type II transitional B cells in the spleen

decreased follicular B cell number ( J:118522 )

decreased IgG1 level ( J:118522 )

• following exposure to human peripheral blood lymphocytes

endocrine/exocrine glands

decreased pancreatic islet number ( J:162641 )

• 2-fold reduction in the percentage of large islets

decreased insulin secretion ( J:162641 )

• islets show up to a 60% reduction in insulin secretion in response to glucose, KCI, exendin 4, forskolin and 8-bromo-cAMP

Genotype
MGI:4366727

hm4

• Allelic Composition: Bmal1^tm1Bra/Bmal1^tm1Bra
• Genetic Background: involves: 129/Sv * C57BL/6 * C57BL/6J

Altered cell cycle progression in the secondary hair germ of hair follicles of Bmal1^tm1Bra/Bmal1^tm1Bra and Clock^m1Jt/Clock^m1Jt mice

integument

abnormal hair follicle matrix region morphology ( J:151782 )

• hair follicles of mutant mice contain a thickened keratinocyte strand between the dermal papilla and the club hair but lack the highly proliferative matrix required for downward growth of the hair follicle during anagen

abnormal hair cycle ( J:151782 )

• mice exhibit a delay in the first synchronized anagen that persists through out the hair cycle

• however, the duration of the hair cycle is normal

abnormal hair cycle anagen phase ( J:151782 )

• the first synchronized anagen is delayed compared to in wild-type mice

Genotype
MGI:5302034

ht5

• Allelic Composition: Bmal1^tm1Bra/Bmal1⁺
• Genetic Background: involves: 129 * C57BL/6

behavior/neurological

delayed circadian behavior phase ( J:177916 )

• significantly enhanced phase delays to light exposure beginning at expected dark (ZT12) with modest enhancements at low irradiance levels and more pronounced delays at higher irradiance levels

Genotype
MGI:5297480

cn6

• Allelic Composition: Bmal1^tm1Bra/Bmal1^tm1Weit; Syt10^{tm1.1(icre)Geno}/Syt10⁺
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJaeSor * C57BL/6

behavior/neurological

abnormal circadian behavior ( J:175596 )

• animals display impaired activity rhythms but are not totally arrhythmic

shortened circadian behavior period ( J:175596 )

• animals have a shorter period in constant light conditions (DD); mutants have higher onset errors than wild-type controls

Genotype
MGI:5297485

cn7

• Allelic Composition: Bmal1^tm1Bra/Bmal1^tm1Weit; Syt10^{tm1.1(icre)Geno}/Syt10^{tm1.1(icre)Geno}
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJaeSor * C57BL/6

behavior/neurological

abnormal circadian behavior ( J:175596 )

• almost all animals display essentially no circadian rhythmicity (no clear circadian peak)

• under light-dark conditions (LD; 12:12 light/dark cycle), mutants are more active than wild-type in the light phase

• in animals, decreasing circadian amplitudes correlate with increasing ultradian amplitudes

Genotype
MGI:5302035

cx8

• Allelic Composition: Bmal1^tm1Bra/Bmal1⁺; Usp2^tm1.1Bjc/Usp2⁺
• Genetic Background: involves: 129 * C57BL/6

behavior/neurological

delayed circadian behavior phase ( J:177916 )

• significantly enhanced phase delays to light exposure beginning at expected dark (ZT12) at low irradiance levels but not at higher irradiance levels

Genotype
MGI:5297481

cx9

• Allelic Composition: Bmal1^tm1Bra/Bmal1^tm1Bra; Syt10^{tm1.1(icre)Geno}/Syt10^{tm1.1(icre)Geno}
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJaeSor * C57BL/6

behavior/neurological

abnormal circadian behavior ( J:175596 )

• mice show no clear circadian peak

• in animals, decreasing circadian amplitudes correlate with increasing ultradian amplitudes

Genotype
MGI:3714773

cx10

• Allelic Composition: Bmal1^tm1Bra/Bmal1^tm1Bra; Tg(Scg2-tTA)1Jt/0; Tg(tetO-Arntl)1Jt/0
• Genetic Background: involves: 129/Sv * C57BL/6J * CD-1

behavior/neurological

behavior/neurological phenotype ( J:116189 )

N • rescued mice exhibit a consistent circadian rhythm (without doxycycline-treatment) which is abolished within 1 to 2 days of doxycycline treatment, then regained after doxycycline withdrawal

abnormal locomotor activation ( J:116189 )

• although circadian rhythm is restored, level activity and amplitude are significantly lower than observed in wild-type

shortened circadian behavior period ( J:116189 )

• free-running period of rescued mice (bitransgenic null mice without doxycycline treatment) is about 1 hour shorter than in wild-type

Genotype
MGI:3714769

cx11

• Allelic Composition: Bmal1^tm1Bra/Bmal1^tm1Bra; Tg(ACTA1-Arntl)1Jt/0
• Genetic Background: involves: 129/Sv * C57BL/6J * CD-1

mortality/aging

mortality/aging ( J:116189 )

N • 100% of rescued mice survive to end of experiment (>10 months) compared to 29% of Arntl-null mice

behavior/neurological

abnormal circadian behavior ( J:116189 )

• mice with muscle rescue do not show circadian rhythmicity of activity, but level of activity is not significantly different from wild-type mice

growth/size/body

decreased body size ( J:116189 )

• at 4 to 6 months of age, rescued mice body weight is lower than wild-type, but not really significantly

skeleton

calcified calcaneal tendon ( J:116189 )

• significant calcaneal tendon calcification is observed in rescued mice similar to Arntl-null animals

muscle

calcified calcaneal tendon ( J:116189 )

• significant calcaneal tendon calcification is observed in rescued mice similar to Arntl-null animals