mammalian phenotype

• hematopoietic system phenotype
  • Normal - at P0, homozygotes display normal erythrocyte counts and morphology as well as normal hemoglobin synthesis relative to wild-type controls
  (MGI Ref ID J:166788)

mortality/aging

• neonatal lethality, incomplete penetrance
  • most homozygotes die during the day of birth; however, normal Mendelian ratios are obtained between E10.5 and E18.5
  (MGI Ref ID J:166788)
  • treatment of pregnant mice with cyclopamine (a smoothened antagonist) from E17.5 significantly increases the % of homozygotes surviving the immediate neonatal period
  (MGI Ref ID J:166788)

respiratory system phenotype

• abnormal pulmonary alveolus morphology
  • several hours after birth, homozygotes display reduced alveolar spaces relative to wild-type controls
  (MGI Ref ID J:166788)

• atelectasis
  • early after birth, mutant lungs are less inflated than wild-type lungs
  (MGI Ref ID J:166788)

• thick pulmonary interalveolar septum
  • several hours after birth, homozygotes display thickened interalveolar septae relative to wild-type controls
  (MGI Ref ID J:166788)

• abnormal lung development
  • Normal - however, pulmonary vascular development is not significantly altered as shown by normal capillary density
  (MGI Ref ID J:166788)
  • homozygotes show an early postnatal defect in lung maturation due to enhanced sonic hedgehog (SHH) signaling
  (MGI Ref ID J:166788)

• decreased lung weight
  • at P0, lung weight is significantly lower than that in wild-type controls
  (MGI Ref ID J:166788)

• respiratory failure
  • homozygotes exhibit early postnatal respiratory failure
  (MGI Ref ID J:166788)
  • Normal - however, a normal spontaneous breathing rate is observed immediately after birth
  (MGI Ref ID J:166788)

• increased mesenchymal cell proliferation involved in lung development
  • 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
  (MGI Ref ID J:166788)
  • inhibition of enhanced SHH signaling by the smoothened antagonist cyclopamine rescues the lung morphology and altered gene expression in P1 mutant mice
  (MGI Ref ID J:166788)
  • enhanced sonic hedgehog (SHH) signaling results in increased mesenchymal proliferation
  (MGI Ref ID J:166788)

cardiovascular system phenotype

• dilated heart right ventricle
  • Normal - 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
  (MGI Ref ID J:166788)
  • at P0, the right ventricle is significantly dilated relative to that in wild-type hearts
  (MGI Ref ID J:166788)

cellular phenotype

• increased mesenchymal cell proliferation involved in lung development
  • enhanced sonic hedgehog (SHH) signaling results in increased mesenchymal proliferation
  (MGI Ref ID J:166788)
  • 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
  (MGI Ref ID J:166788)
  • inhibition of enhanced SHH signaling by the smoothened antagonist cyclopamine rescues the lung morphology and altered gene expression in P1 mutant mice
  (MGI Ref ID J:166788)

growth/size/body region phenotype

• slow postnatal weight gain
  • newborn homozygotes gain weight more slowly than wild-type controls
  (MGI Ref ID J:166788)
  • Normal - however, drinking behavior is normal, as shown by the presence of gastric milk
  (MGI Ref ID J:166788)

• decreased birth weight
  • at P0, body weight is significantly lower than that in wild-type controls
  (MGI Ref ID J:166788)

homeostasis/metabolism phenotype

• cyanosis
  • homozygotes become cyanotic within hours of birth
  (MGI Ref ID J:166788)

mammalian phenotype

• cardiovascular system phenotype
  • Normal - consistent with these findings, direct mean arterial pressure was significantly lower in subtotally nephrectomized heterozygous mutant mice relative to wild-type littermates
  (MGI Ref ID J:89315)
  • Normal - 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 (8.1¿2.44 versus 39.4¿6.83 mm Hg, respectively)
  (MGI Ref ID J:89315)
  • Normal - 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
  (MGI Ref ID J:89315)
  • Normal - tes
  (MGI Ref ID J:89315)
  • Normal - nd a significantly lower change in blood pressure (8.1¿2.44 versus 39.4¿6.83 mm Hg, respectively)
  (MGI Ref ID J:89315)

• renal/urinary system phenotype
  • Normal - 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
  (MGI Ref ID J:89315)

mortality/aging

• postnatal lethality
  • homozygous null mice were viable, fertile and grossly normal, but were recovered from heterozygous crosses at less than the predicted Mendelian ratios
  (MGI Ref ID J:34819)
  • homozygous null mice displayed poorer survival; no specific reason for this poor survival has been reported
  (MGI Ref ID J:34819)

muscle phenotype

• abnormal vasoconstriction
  • 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
  (MGI Ref ID J:34819)
  • 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
  (MGI Ref ID J:34819)
  • radycardia; 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
  (MGI Ref ID J:34819)
  • notably, mutant mice exhibited an absence of alpha2-mediated peripheral vasoconstriction
  (MGI Ref ID J:34819)

reproductive system phenotype

• abnormal fertility/fecundity
  • homozygous null mice did not breed well compared with wild-type littermates
  (MGI Ref ID 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
  (MGI Ref ID J:58591)

cardiovascular system phenotype

• abnormal 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
  (MGI Ref ID J:34819)
  • notably, mutant mice exhibited an absence of alpha2-mediated peripheral vasoconstriction
  (MGI Ref ID J:34819)
  • radycardia; 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
  (MGI Ref ID J:34819)
  • 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
  (MGI Ref ID J:34819)

mammalian phenotype

• behavior/neurological phenotype
  • Normal - also, dexmedetomidine induced normal dose-dependent antinociception in homozygous null mice in the hot-water tail immersion test
  (MGI Ref ID J:89316)
  • Normal - in response to dexmedetomidine, homozygous null mice showed normal dose-dependent reductions in locomotor activity
  (MGI Ref ID J:89316)

• cardiovascular system phenotype
  • Normal - unrestrained, conscious mutant animals displayed no significant changes in mean arterial pressure or heart rate at baseline
  (MGI Ref ID J:34819)
  • Normal - ificantly elevated levels of norepinephrine in these mice
  (MGI Ref ID J:89317)
  • Normal - 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
  (MGI Ref ID J:89317)

• homeostasis/metabolism phenotype
  • Normal - in response to dexmedetomidine, homozygous null mice showed normal dose-dependent reductions in body temperature
  (MGI Ref ID J:89316)