Analysis Tools
mortality/aging
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• if left untreated, homozygotes die by 8 hrs post-partum from hypoglycemia
• hypoglycemic newborns can be maintained until P2 by subcutaneous injections of glucose but rarely survive beyond 40 hrs, despite normal suckling behavior and presence of normal volumes of gastric milk
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• most homozygotes survive to term; however, homozygotes are obtained at a reduced frequency at birth (20.5% vs 25%), indicating embryonic/perinatal loss
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digestive/alimentary system
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• newborn homozygotes transiently rescued by glucose injections exhibit normal structural and functional maturation of the small intestine, with no significant differences in mucosal architecture or in the size of proliferative zone in intestinal crypts
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growth/size/body
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• at 32 hrs post-partum, glucose-treated homozygotes fail to increase their birth weights as efficiently as wild-type or heterozygous mutant mice (~9.6% vs ~32.4%)
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• newborn homozygotes transiently rescued by glucose injections gain little weight relative to wild-type mice
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homeostasis/metabolism
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• at 32 hrs post-partum, homozygotes show a ~4-fold increase in serum tyrosine levels relative to wild-type mice
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• at 2 hrs post-partum, homozygotes display a 50% reduction in albumin mRNA levels relative to wild-type mice; levels remain low at 7 and 32 hrs post-partum
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• newborn homozygotes exhibit severe derangements of energy metabolism resulting from a lack of triacylglycerol storage in adipose tissue and glycogen storage in the liver
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hypoglycemia
(
J:28320
)
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• homozygotes exhibit reduced glucose concentrations as early as 1-2 hrs post-partum, and remain hypoglycemic at 5-8 hrs with glucose concentrations of only 0.61.3 mg/dl
• neonatal hypoglycemia is partly attributed to an observed delay in transactivation of PEPCK and G6Pase
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• homozygotes exhibit delayed transactivation of PEPCK and G6Pase
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• homozygotes exhibit impaired prenatal and postnatal glycogen synthesis
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• at E18.5 and at 1 hr post-partum, homozygotes contain virtually no glycogen in the liver, whereas wild-type mice contain abundant glycogen
• at 32 hrs post-partum, glucose-injected homozygotes fail to exhibit abundant hepatic glycogen
• absence of hepatic glycogen is associated with a 50-70% reduction in glycogen synthase mRNA
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• homozygotes show lack of triacylglycerol storage in adipose tissue, probably as a result of abnormal lipid processing or storage
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respiratory system
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• histologically, mutant lungs appear immature relative to wild-type lungs
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• neonatal mutant lungs display excessive accumulation of surfactant material in the alveoli
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• neonatal mutant lungs exhibit hyperproliferation of alveolar type II (SP-C-positive) cells
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• neonatal mutant lungs display a significantly hyperplastic alveolar wall with many alveolar cells
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• neonatal mutant lungs display overexpression of surfactant protein SP-A, SP-B and SP-C mRNAs as determined by immunohistochemistry, in situ hybridization, and Northern blot analysis
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behavior/neurological
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• homozygotes exhibit lethargy several hours after birth
• however, mutant neonates appear grossly normal with no significant alterations in major organ morphology or birth weights
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• mutant pups contain little or no milk in their stomachs, probably as a result of lack of energy for nourishment
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adipose tissue
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• at 32 hrs post-partum, homozygotes fail to display an increase in the volume of interscapular brown adipose tissue; no large lipid droplets are observed, suggesting abnormal adipocyte maturation
• in addition, the expression of the Ucp1 gene for uncoupling protein-1, a marker of brown adipose tissue, is reduced
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• at 15 min and 32 hrs post-partum, homozygotes fail to show lipid accumulation in subcutaneous inguinal white adipose tissue
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liver/biliary system
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• at 32 hrs post-partum, glucose-injected homozygotes exhibit hepatocytes with reduced lipid accumulation and glycogen storage relative to wild-type mice
• no significant differences in serum alanine transaminase or alanine phosphatase activities are observed, indicating absence of hepatic injury or necrosis
• no bile thrombi or cholestasis are observed
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• at E18.5 and at 1 hr post-partum, homozygotes contain virtually no glycogen in the liver, whereas wild-type mice contain abundant glycogen
• at 32 hrs post-partum, glucose-injected homozygotes fail to exhibit abundant hepatic glycogen
• absence of hepatic glycogen is associated with a 50-70% reduction in glycogen synthase mRNA
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• mutant hepatocyte rosettes display decreased cellular volumes and dilated biliary canaliculi with shorter and fewer microvilli than wild-type mice
• as a result, mitochondria and the endoplasmic reticulum appear densely packed
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