title: Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman syndrome are dependent on maternal and dietary influences.
abstract: Angelman syndrome (AS) is a neurodevelopmental disorder characterized by a number of neurological problems, including developmental delay, movement disorders, and epilepsy. AS results from the loss of UBE3A (an imprinted gene) expressed from the maternal chromosome in neurons. Given the ubiquitous expression of Ube3a and the devastating nature of AS, the role of environmental and maternal effects has been largely ignored. Severe ataxia, anxiety-like behaviors and learning deficits are well-documented in patients and AS mice. More recently, clinical imaging studies of AS patients suggest myelination may be delayed or reduced. Utilizing a mouse model of AS, we found disrupted expression of cortical myelin proteins, the magnitude of which is influenced by maternal status, in that the aberrant myelination in the AS pups of AS affected mothers were more pronounced than those seen in AS pups raised by unaffected (Ube3a (m+/p-)) Carrier mothers. Furthermore, feeding the breeding mothers a higher fat (11% vs 5%) diet normalizes these myelin defects. These effects are not limited to myelin proteins. Since AS mice have abnormal stress responses, including altered glucocorticoid receptor (GR) expression, we measured GR expression in pups from Carrier and affected AS mothers. AS pups had higher GR expression than their WT littermates. However, we also found an effect of maternal status, with reduced GR levels in pups from affected mothers compared to genotypically identical pups raised by unaffected Carrier mothers. Taken together, our findings suggest that the phenotypes observed in AS mice may be modulated by factors independent of Ube3a genotype.
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232-8552, USA. Electronic address: Mark.Grier@vanderbilt.edu.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Grier
authors.affiliation: Department of Pediatrics and Neurology, Vanderbilt University Medical Center, Nashville, TN 37232-8552, USA. Electronic address: Robert.Carson@vanderbilt.edu.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Carson
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232-8552, USA; Department of Neurology, Tennessee Valley Veterans Administration, Nashville, TN 37212, USA. Electronic address: Andre.H.Lagrange@vanderbilt.edu.
authors.forename: Andre H
authors.initials: AH
authors.lastname: Lagrange
mesh_terms: D017204:Angelman Syndrome / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D006579:Heterozygote; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000378:metabolism*; D010641:Phenotype; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics
chemical_list: D009185:Myelin Proteins; D011965:Receptors, Glucocorticoid; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Angelman syndrome; Breeding; E6AP; Maternal effects; Myelin; Ube3a