Journal
JOURNAL OF NEUROSCIENCE
Volume 37, Issue 31, Pages 7347-7361Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0037-17.2017
Keywords
Angelman; axon; E6-AP; microcephaly; UBE3A; white matter
Categories
Funding
- National Institutes of Health [5F32NS077686]
- Angelman Syndrome Foundation
- National Institute of Neurological Disorders and Stroke- National Institutes of Health (NINDS) [5R01NS039444, 1R01NS085093]
- NINDS [P30 NS045892]
- NICHD Center Grant [P30 HD03110]
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Angelman syndrome (AS) is a debilitating neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A allele. It is currently unclear how the consequences of this genetic insult unfold to impair neurodevelopment. We reasoned that by elucidating the basis of microcephaly in AS, a highly penetrant syndromic feature with early postnatal onset, we would gain new insights into the mechanisms by which maternal UBE3A loss derails neurotypical brain growth and function. Detailed anatomical analysis of both male and female maternal Ube3a-null mice reveals that microcephaly in the AS mouse model is primarily driven by deficits in the growth of white matter tracts, which by adulthood are characterized by densely packed axons of disproportionately small caliber. Our results implicate impaired axon growth in the pathogenesis of AS and identify noninvasive structural neuroimaging as a potentially valuable tool for gauging therapeutic efficacy in the disorder.
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