Analysis Tools
mortality/aging
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• the majority of mice fail to make the transition to grain
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• many mice die between 19 and 35 days after birth
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• some mice die before weaning
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growth/size/body
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• may be reduced, as body weight is reduced 25-30% and adipose tissue is ~15% of body weight
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• by third day after birth, mice display significantly reduced weigh gain, and remain 25-30% underweight throughout their lifetime
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• by P3, mutants can be identified by their distended abdomens
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• liver is 2-fold larger than wild-type in neonates, and 20% larger in adults
(J:63448)
• homozygotes can be recognized as early as P3 by their large livers
(J:82882)
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behavior/neurological
limb grasping
(
J:82882
)
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• when lifted by the tail, mice clench toes of the hind feet and clasp hind limbs together
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• adults lack hind limb coordination
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abnormal gait
(
J:82882
)
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• homoyzgotes develop an unsteady gait starting at ~P10, and this persists throughout life
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nervous system
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• numerous hypertrophic cells with increased nuclear size, abnormally large mitochondria and copius cytoplasm are observed, and some cells contain myelin degradation debris; this becomes more widely distributed by 30 days and persist through 1 year
• abnormal cells are more common in older mice
• in adults, free cell processes and basal lamina are frequently found, but onion bulb formation is rare
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• sheaths around axons of the sciatic nerve at postnatal day 4 are markedly thin compared to controls; this persists through 1 year of age
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• axonal myelin sheaths are thin, hypertrophic Schwann cells are observed, sometimes accumulating myelin debris with age
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• in adult sciatic nerves, some degenerating axons are observed, along with bands of Bugner, and regenerative clusters occasionally
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reproductive system
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• females do not generally produce their first litter until ~90 days of age
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• ~50% of females are infertile
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• all males appear to be infertile, possibly due to behavior impairment
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adipose tissue
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• in adults and neonates, tissue appears abnormal
• brown adipose tissue sections at 1 and 6 months of age exhibit dramatically reduced lipid content relative to controls; in some regions, tissue consists largely of muscle with small masses of lipid-poor adipocytes
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• mice exhibit reduced fat mass in brown adipose tissue depots
(J:63448)
• interscapular brown adipose tissue mass is reduced 80% in adults, but not in neonates
(J:63448)
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• at 1 and 6 months of age, adipocytes are found to be severely depleted of lipid
(J:63448)
• by 6 months, white adipocytes have accumulated more lipid than at 1 month, but cells remain reduced in size and contain a heterogeneous population of lipid droplets characteristic of incompletely differentiated adipocytes
(J:63448)
• in some regions of brown adipose tissue sections at 1 and 6 months of age, tissue consists largely of muscle with small masses of lipid-poor adipocytes
(J:63448)
• adipocytes appear immature with sparse lipid droplets
(J:66739)
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• epididymal fat pads from 1-month old mice have immature cells containing mostly small, sparse lipid droplets
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• epididymal fat pad mass is reduced ~80% in neonates and adults
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• fat pad mass is reduced ~80% in neonates and adults
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• interscapular brown adipose tissue mass is reduced 80% in adults, but not in neonates
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• mice exhibit reduced fat mass in white adipose tissue depots
(J:63448)
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• brown adipose tissue levels of uncoupling protein 1 mRNA are reduced
• PPARgamma and adipocyte fatty acid-binding protein aP2 mRNA levels are markedly elevated in mutants, most evident at 2 weeks of age and less pronounced in older mice
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• white adipose tissue expresses reduced mRNA levels of lipoprotein lipase, as well as adipsin and uncoupling protein 1
• after weaning, expression of fatty acid synthase and acetyl-CoA carboxylase is relatively unchanged compared to wild-type where expression is highly induced
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cardiovascular system
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• after 16 weeks of an atherogenic diet, mutants display 2-fold greater lesion area relative to wild-type littermates; lesions are qualitatively more advanced than in wild-type
• lesions extend beyond aortic valve attachment points to form raised lesions in the free aortic wall
• raised lesions are detected in 92% of homozygotes vs only 44% of wild-type mice
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homeostasis/metabolism
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• 60 minutes following glucose injection, mutant insulin levels are slightly higher than in wild-type but lower than that measured in non-glucose-challenged mutants indicating impaired secretion
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• nonfasting insulin levels are elevated 2.5-fold in mutants on a regular chow diet
• on an atherogenic diet for 16 weeks, insulin levels in plasma are reduced in mutants and wild-type, but levels in mutant mice are 4-fold higher than in wild-type
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• plasma leptin levels are significantly reduced
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• mice have impaired clearance of a glucose dose with levels remaining >400 mg/dl for 2 hours after glucose administration, in contrast to levels in wild-type mice which return to baseline after 1 hour
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• administration of exogenous insulin with glucose injection does not produce the typical hypoglycemic response seen in wild-type
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• sphingomyelin and galactosphingolipids and sulfatides exhibit age-dependent decreases in levels relative to phosphotidylcholine in mutants but not in wild-type
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• mice have increased cholesterol ester levels in sciatic nerve extracts at 1-2 and 3+ months of age relative to wild-type
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• within several days of birth, hepatic levels of apolipoprotein ApoA-IV mRNA are increased 100-fold and ApoC-II mRNA levels are 6-fold increased relative to wild-type
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• on an atherogenic diet, the LDL/VLDL fraction (60%) makes up less of the total cholesterol compared to wild-type (76%)
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• on an atherogenic diet for 16 weeks, the LDL/VLDL fraction (60%) makes up less of the total cholesterol compared to wild-type (76%)
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• levels are significantly less in sciatic nerve lipids (552, 226 ng/ug) vs wild-type (896, 526 ng/ug) at 1-2 months and 3+ months respectively
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• on an atherogenic diet for 16 weeks, the HDL fraction (40% of total) accounts for more cholesterol than in wild-type (24%)
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• in response to atherogenic diet, mutants have slightly lower fatty acid levels than wild-type
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• levels in sciatic nerve extracts are 2-fold higher than wild-type at 3+ months of age
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• at 3 months of age, sciatic nerve lipids show an elevation of neutral lipid species and alteration of relative amounts of phosphatidylserine, phophatidyl- or phophatidalethanolamine, phophatidylcholine, and sphingomyelin compared to control levels
• phosphotidylinositol:phosphotidylcholine ratio is slightly increased in mutant nerves relative to wild-type
• lipid profile resembles that of an immature nerve or one undergoing repair
• at 3+ months of age, phosphatidylcholine levels in sciatic nerve extracts are 3.3 times the level in wild-type, while levels of phosphatidal- and phosphotidylethanolamines and phosphotidalserine are lower than controls at all ages, and difference from wild type increases with age
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• at 3+ months, ratio of triglycerides to cholesterol in sciatic nerves is slightly lower than wild-type
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• within a few days after birth, serum triglyceride levels are elevated by several fold relative to controls
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• adult hepatocytes secrete more VLDL-sized apoB48-containing particles than do hepatocytes from littermate controls, and hepatic overexpression of lipin 1 markedly suppresses triglyceride secretion resulting in less VLDL-sized particles and more HDL-like particles
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• within a few days after birth, hepatic triglyceride levels are elevated by several fold relative to controls
(J:82882)
• hepatocytes isolated from 14 day old homozygotes have significantly increased triglyceride synthesis and secretion rates
(J:147417)
• hepatoctyes isolated from 42 day old adult homozygotes have normal synthesis but increased secretion of triglycerides
(J:147417)
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• in 3-week old mice, hormone-sensitive lipase activity is reduced ~50% compared to wild-type tissue (29 vs 60 mU/mg)
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• hepatic lipase activity and mRNA levels are reduced ~6-fold and 2-fold respectively compared to wild-type: abnormalities resolve between 14 and 28 days postnatal
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• during the suckling period, lipoprotein lipase activity is reduced by ~16-fold in white adipose tissue and by <2-fold in the heart of mutants
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liver/biliary system
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• liver is 2-fold larger than wild-type in neonates, and 20% larger in adults
(J:63448)
• homozygotes can be recognized as early as P3 by their large livers
(J:82882)
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• within a few days after birth, hepatic triglyceride levels are elevated by several fold relative to controls
(J:82882)
• hepatocytes isolated from 14 day old homozygotes have significantly increased triglyceride synthesis and secretion rates
(J:147417)
• hepatoctyes isolated from 42 day old adult homozygotes have normal synthesis but increased secretion of triglycerides
(J:147417)
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pale liver
(
J:82882
)
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• homozygotes can be recognized as early as P3 by their pale livers
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endocrine/exocrine glands
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• 60 minutes following glucose injection, mutant insulin levels are slightly higher than in wild-type but lower than that measured in non-glucose-challenged mutants indicating impaired secretion
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integument
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• ruffled coat appearance is due to reduced hair growth
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• mice have unkempt coat appearance
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ruffled hair
(
J:82882
)
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• mice have coats with ruffled appearance
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