Phenotypes associated with this allele

• Allele Symbol: Adra2b^tm1Gsb
• Allele Name: targeted mutation 1, Gregory S Barsh
• Allele ID: MGI:1857118
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Adra2b^tm1Gsb/Adra2b^tm1Gsb	B6.129-Adra2b^tm1Gsb	MGI:4950663
hm2	Adra2b^tm1Gsb/Adra2b^tm1Gsb	involves: 129S1/Sv * 129X1/SvJ * C57BL/6J	MGI:3039497
ht3	Adra2b^tm1Gsb/Adra2b^+	involves: 129S1/Sv * 129X1/SvJ * C57BL/6J	MGI:3039644
cx4	Adra2a^tm1Bkk/Adra2a^tm1Bkk Adra2b^tm1Gsb/Adra2b^tm1Gsb Adra2c^tm1Gsb/Adra2c^tm1Gsb	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2J	MGI:3039647

Genotype
MGI:4950663

hm1

• Allelic Composition: Adra2b^tm1Gsb/Adra2b^tm1Gsb
• Genetic Background: B6.129-Adra2b^tm1Gsb

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

Dilated right ventricle in Adra2b^tm1Gsb/Adra2b^tm1Gsb mice

mortality/aging

neonatal lethality, incomplete penetrance ( J:166788 )

• most homozygotes die during the day of birth; however, normal Mendelian ratios are obtained between E10.5 and E18.5

• treatment of pregnant mice with cyclopamine (a smoothened antagonist) from E17.5 significantly increases the % of homozygotes surviving the immediate neonatal period

growth/size/body

decreased birth weight ( J:166788 )

• at P0, body weight is significantly lower than that in wild-type controls

slow postnatal weight gain ( J:166788 )

• newborn homozygotes gain weight more slowly than wild-type controls

• however, drinking behavior is normal, as shown by the presence of gastric milk

homeostasis/metabolism

cyanosis ( J:166788 )

• homozygotes become cyanotic within hours of birth

respiratory system

abnormal lung development ( J:166788 )

• homozygotes show an early postnatal defect in lung maturation due to enhanced sonic hedgehog (SHH) signaling

• however, pulmonary vascular development is not significantly altered as shown by normal capillary density

increased mesenchymal cell proliferation involved in lung development ( J:166788 )

• enhanced sonic hedgehog (SHH) signaling results in increased mesenchymal proliferation

• at P0, mutant lungs show a significant increase in the rate of mitosis and expression of cell cycle regulators cyclin D1 and Ki67 relative to wild-type lungs

• inhibition of enhanced SHH signaling by the smoothened antagonist cyclopamine rescues the lung morphology and altered gene expression in P1 mutant mice

decreased lung weight ( J:166788 )

• at P0, lung weight is significantly lower than that in wild-type controls

abnormal pulmonary alveolus morphology ( J:166788 )

• several hours after birth, homozygotes display reduced alveolar spaces relative to wild-type controls

atelectasis ( J:166788 )

• early after birth, mutant lungs are less inflated than wild-type lungs

thick pulmonary interalveolar septum ( J:166788 )

• several hours after birth, homozygotes display thickened interalveolar septae relative to wild-type controls

respiratory failure ( J:166788 )

• homozygotes exhibit early postnatal respiratory failure

• however, a normal spontaneous breathing rate is observed immediately after birth

cardiovascular system

dilated heart right ventricle ( J:166788 )

• at P0, the right ventricle is significantly dilated relative to that in wild-type hearts

• however, cardiac structure and function is normal with no significant differences in cardiac rhythm, ECG recordings or closure of the ductus arteriosus relative to wild-type controls

hematopoietic system

hematopoietic system phenotype ( J:166788 )

N • at P0, homozygotes display normal erythrocyte counts and morphology as well as normal hemoglobin synthesis relative to wild-type controls

cellular

increased mesenchymal cell proliferation involved in lung development ( J:166788 )

• enhanced sonic hedgehog (SHH) signaling results in increased mesenchymal proliferation

• at P0, mutant lungs show a significant increase in the rate of mitosis and expression of cell cycle regulators cyclin D1 and Ki67 relative to wild-type lungs

• inhibition of enhanced SHH signaling by the smoothened antagonist cyclopamine rescues the lung morphology and altered gene expression in P1 mutant mice

Genotype
MGI:3039497

hm2

• Allelic Composition: Adra2b^tm1Gsb/Adra2b^tm1Gsb
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

mortality/aging

postnatal lethality ( J:34819 )

• homozygous null mice were viable, fertile and grossly normal, but were recovered from heterozygous crosses at less than the predicted Mendelian ratios

• homozygous null mice displayed poorer survival; no specific reason for this poor survival has been reported

behavior/neurological

behavior/neurological phenotype ( J:89316 )

N • in response to dexmedetomidine, homozygous null mice showed normal dose-dependent reductions in locomotor activity

N • also, dexmedetomidine induced normal dose-dependent antinociception in homozygous null mice in the hot-water tail immersion test

cardiovascular system

cardiovascular system phenotype ( J:34819 , J:89317 )

N • unrestrained, conscious mutant animals displayed no significant changes in mean arterial pressure or heart rate at baseline (J:34819)

N • when subjected to bilateral nephrectomy followed by acute saline loading, anephric homozygous null mice were unable to raise their blood pressure, as expected, and displayed a slightly lowered blood pressure at the end of the infusion period, despite significantly elevated levels of norepinephrine in these mice (J:89317)

abnormal vasoconstriction ( J:34819 )

• notably, mutant mice exhibited an absence of alpha2-mediated peripheral vasoconstriction

• specifically, in wild-type mice, the arterial blood pressure response to dexmedetomidine (an alpha2-adrenergic receptor agonist) was typified by an immediate hypertensive response, followed by a long-lasting hypotensive response, as well as an immediate bradycardia; in contrast, in homozygous null mice, the hypertensive response was abolished, and the hypotensive effect was immediate and accentuated, whereas the bradycardic response was normal relative to wild-type

• homozygous null mice exhibited a normal hypertensive response to challenge with a non-selective alpha1 agonist (phenylephrine), indicating a normal vasoconstrictive response to alpha1-adrenergic receptor stimulation

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:89316 )

N • in response to dexmedetomidine, homozygous null mice showed normal dose-dependent reductions in body temperature

reproductive system

abnormal fertility/fecundity ( J:34819 , J:58591 )

• homozygous null mice did not breed well compared with wild-type littermates (J:34819)

• poor survival and breeding suggesting some developmental or reproductive deficit was corroborated by the inability to produce either Adra2a/Adra2b or Adra2b/Adra2c double homozygous null mice (J:58591)

muscle

abnormal vasoconstriction ( J:34819 )

• notably, mutant mice exhibited an absence of alpha2-mediated peripheral vasoconstriction

• specifically, in wild-type mice, the arterial blood pressure response to dexmedetomidine (an alpha2-adrenergic receptor agonist) was typified by an immediate hypertensive response, followed by a long-lasting hypotensive response, as well as an immediate bradycardia; in contrast, in homozygous null mice, the hypertensive response was abolished, and the hypotensive effect was immediate and accentuated, whereas the bradycardic response was normal relative to wild-type

• homozygous null mice exhibited a normal hypertensive response to challenge with a non-selective alpha1 agonist (phenylephrine), indicating a normal vasoconstrictive response to alpha1-adrenergic receptor stimulation

Genotype
MGI:3039644

ht3

• Allelic Composition: Adra2b^tm1Gsb/Adra2b⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

cardiovascular system

cardiovascular system phenotype ( J:89315 )

N • when subjected to subtotal nephrectomy followed by dietary salt loading, heterozygous mutant mice displayed an attenuated hypertensive response, resulting in a significantly lower end-point tail-cuff blood pressure compared with their wild-type controls and a significantly lower change in blood pressure (8.12.44 versus 39.46.83 mm Hg, respectively)

N • consistent with these findings, direct mean arterial pressure was significantly lower in subtotally nephrectomized heterozygous mutant mice relative to wild-type littermates

N • heterozygous mutant mice displayed no difference in baseline blood pressure (prior to subtotal nephrectomy) relative to wild-type littermates; similarly, heterozygotes showed no difference in baseline or end-point heart rate relative to wild-type littermates

renal/urinary system

renal/urinary system phenotype ( J:89315 )

N • subtotally nephrectomized heterozygous mutant mice that were given 1% saline as drinking water showed no changes in body weight, ratio of remnant kidney weight to body weight, or plasma creatinine levels relative to wild-type littermates

Genotype
MGI:3039647

cx4

• Allelic Composition: Adra2a^tm1Bkk/Adra2a^tm1Bkk; Adra2b^tm1Gsb/Adra2b^tm1Gsb; Adra2c^tm1Gsb/Adra2c^tm1Gsb
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2J

mortality/aging

embryonic lethality during organogenesis, complete penetrance ( J:77486 )

• triple homozygous mutant embryos died between E9.5-E11.5

cardiovascular system

cardiovascular system phenotype ( J:77486 )

N • at E9.5, triple mutant embryos had a normal heart rate and a normal cardiac structure

decreased heart rate ( J:77486 )

• at E10.5, only moribund triple mutant embryos displayed bradycardia

• also, triple mutant embryos had normal concentrations of L-dopa and noradrenaline but exhibited a reduction in basal phosphorylation of mitogen activated protein kinase-1 and -3

embryo

abnormal visceral yolk sac morphology ( J:77486 )

• the yolk sac of triple homozygous mutant embryos was less vascularized and appeared more translucent relative to wild-type

• the endothelial cells in the yolk sac were often detached from the visceral endoderm cell layer

abnormal placenta development ( J:77486 )

• triple mutant mice displayed a significantly reduced density of fetal blood vessels in the placental vascular labyrinth, which leads to embryonic lethality as a result of limited oxygen and nutrient supply