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Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells.

Grier MD, Carson RP, Lagrange AH - PLoS ONE (2015)

Bottom Line: Utilizing enriched primary cultures of oligodendrocytes and astrocytes, we show that Ube3a is expressed, but not imprinted in these cell types.To determine the temporal expression pattern and silencing, we analyzed Ube3a expression in AS mice at several time points.We confirm relaxed imprinting of Ube3a in neurons of the postnatal developing cortex, but not in structures in which neurogenesis and migration are more complete.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232-8552, United States of America.

ABSTRACT
Angelman Syndrome (AS) is a devastating neurodevelopmental disorder characterized by developmental delay, speech impairment, movement disorder, sleep disorders and refractory epilepsy. AS is caused by loss of the Ube3a protein encoded for by the imprinted Ube3a gene. Ube3a is expressed nearly exclusively from the maternal chromosome in mature neurons. While imprinting in neurons of the brain has been well described, the imprinting and expression of Ube3a in other neural tissues remains relatively unexplored. Moreover, given the overwhelming deficits in brain function in AS patients, the possibility of disrupted Ube3a expression in the infratentorial nervous system and its consequent disability have been largely ignored. We evaluated the imprinting status of Ube3a in the spinal cord and sciatic nerve and show that it is also imprinted in these neural tissues. Furthermore, a growing body of clinical and radiological evidence has suggested that myelin dysfunction may contribute to morbidity in many neurodevelopmental syndromes. However, findings regarding Ube3a expression in non-neuronal cells of the brain have varied. Utilizing enriched primary cultures of oligodendrocytes and astrocytes, we show that Ube3a is expressed, but not imprinted in these cell types. Unlike many other neurodevelopmental disorders, AS symptoms do not become apparent until roughly 6 to 12 months of age. To determine the temporal expression pattern and silencing, we analyzed Ube3a expression in AS mice at several time points. We confirm relaxed imprinting of Ube3a in neurons of the postnatal developing cortex, but not in structures in which neurogenesis and migration are more complete. This furthers the hypothesis that the apparently normal window of development in AS patients is supported by an incompletely silenced paternal allele in developing neurons, resulting in a relative preservation of Ube3a expression during this crucial epoch of early development.

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Ube3a is imprinted in brain, spinal cord and sciatic nerve.A) Representative data from cortex, spinal cord and sciatic nerve lysates. B) Lysates from P42 spinal cord and sciatic nerve from AS animals have a reduction of Ube3a expression similar to that seen in cortex. n = 13–19 per group.
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pone.0124649.g001: Ube3a is imprinted in brain, spinal cord and sciatic nerve.A) Representative data from cortex, spinal cord and sciatic nerve lysates. B) Lysates from P42 spinal cord and sciatic nerve from AS animals have a reduction of Ube3a expression similar to that seen in cortex. n = 13–19 per group.

Mentions: Clinical and basic research to date has focused nearly exclusively on disrupted Ube3a in the brain and imprinting in neurons[4]. This is likely due to the fact that the overwhelming morbidity faced by AS patients are related to CNS dysfunction. Moreover, given the presence of peripheral motor reflexes and lack of a clear spinal phenotype, it might easily be assumed that spine and peripheral nerve function are relatively spared AS, although this has not been studied in detail. To determine the imprinting status of Ube3a throughout the neuraxis, we first confirmed the imprinting of Ube3a in P42 murine cortical lysates. We next determined that Ube3a is highly expressed in the spinal cord and sciatic nerve in WT mice and it is significantly reduced in AS mice. As expected, paternal Ube3a is expressed at very low levels, approximately 5–10% of WT in AS mice in all neural tissues assayed (Fig 1A and 1B). Ube3a is not expressed in Ube3a knockout (m-/p-, KO) tissue (S1 Fig). These data confirm that Ube3a is imprinted in both the spinal cord and in peripheral nervous tissue.


Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells.

Grier MD, Carson RP, Lagrange AH - PLoS ONE (2015)

Ube3a is imprinted in brain, spinal cord and sciatic nerve.A) Representative data from cortex, spinal cord and sciatic nerve lysates. B) Lysates from P42 spinal cord and sciatic nerve from AS animals have a reduction of Ube3a expression similar to that seen in cortex. n = 13–19 per group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403805&req=5

pone.0124649.g001: Ube3a is imprinted in brain, spinal cord and sciatic nerve.A) Representative data from cortex, spinal cord and sciatic nerve lysates. B) Lysates from P42 spinal cord and sciatic nerve from AS animals have a reduction of Ube3a expression similar to that seen in cortex. n = 13–19 per group.
Mentions: Clinical and basic research to date has focused nearly exclusively on disrupted Ube3a in the brain and imprinting in neurons[4]. This is likely due to the fact that the overwhelming morbidity faced by AS patients are related to CNS dysfunction. Moreover, given the presence of peripheral motor reflexes and lack of a clear spinal phenotype, it might easily be assumed that spine and peripheral nerve function are relatively spared AS, although this has not been studied in detail. To determine the imprinting status of Ube3a throughout the neuraxis, we first confirmed the imprinting of Ube3a in P42 murine cortical lysates. We next determined that Ube3a is highly expressed in the spinal cord and sciatic nerve in WT mice and it is significantly reduced in AS mice. As expected, paternal Ube3a is expressed at very low levels, approximately 5–10% of WT in AS mice in all neural tissues assayed (Fig 1A and 1B). Ube3a is not expressed in Ube3a knockout (m-/p-, KO) tissue (S1 Fig). These data confirm that Ube3a is imprinted in both the spinal cord and in peripheral nervous tissue.

Bottom Line: Utilizing enriched primary cultures of oligodendrocytes and astrocytes, we show that Ube3a is expressed, but not imprinted in these cell types.To determine the temporal expression pattern and silencing, we analyzed Ube3a expression in AS mice at several time points.We confirm relaxed imprinting of Ube3a in neurons of the postnatal developing cortex, but not in structures in which neurogenesis and migration are more complete.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232-8552, United States of America.

ABSTRACT
Angelman Syndrome (AS) is a devastating neurodevelopmental disorder characterized by developmental delay, speech impairment, movement disorder, sleep disorders and refractory epilepsy. AS is caused by loss of the Ube3a protein encoded for by the imprinted Ube3a gene. Ube3a is expressed nearly exclusively from the maternal chromosome in mature neurons. While imprinting in neurons of the brain has been well described, the imprinting and expression of Ube3a in other neural tissues remains relatively unexplored. Moreover, given the overwhelming deficits in brain function in AS patients, the possibility of disrupted Ube3a expression in the infratentorial nervous system and its consequent disability have been largely ignored. We evaluated the imprinting status of Ube3a in the spinal cord and sciatic nerve and show that it is also imprinted in these neural tissues. Furthermore, a growing body of clinical and radiological evidence has suggested that myelin dysfunction may contribute to morbidity in many neurodevelopmental syndromes. However, findings regarding Ube3a expression in non-neuronal cells of the brain have varied. Utilizing enriched primary cultures of oligodendrocytes and astrocytes, we show that Ube3a is expressed, but not imprinted in these cell types. Unlike many other neurodevelopmental disorders, AS symptoms do not become apparent until roughly 6 to 12 months of age. To determine the temporal expression pattern and silencing, we analyzed Ube3a expression in AS mice at several time points. We confirm relaxed imprinting of Ube3a in neurons of the postnatal developing cortex, but not in structures in which neurogenesis and migration are more complete. This furthers the hypothesis that the apparently normal window of development in AS patients is supported by an incompletely silenced paternal allele in developing neurons, resulting in a relative preservation of Ube3a expression during this crucial epoch of early development.

Show MeSH
Related in: MedlinePlus