Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice
Lei Xing,
Jeremy M. Simon,
Travis S. Ptacek,
Jason J. Yi,
Lipin Loo,
Hanqian Mao,
Justin M. Wolter,
Eric S. McCoy,
Smita R. Paranjape,
Bonnie Taylor-Blake,
Mark J. Zylka
Affiliations
Lei Xing
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Jeremy M. Simon
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Campus Box #7255, Chapel Hill, NC 27599, USA; Department of Genetics, The University of North Carolina at Chapel Hill, Campus Box #7264, Chapel Hill, NC 27599, USA
Travis S. Ptacek
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Campus Box #7255, Chapel Hill, NC 27599, USA
Jason J. Yi
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Campus Box #7255, Chapel Hill, NC 27599, USA
Lipin Loo
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Hanqian Mao
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Campus Box #7255, Chapel Hill, NC 27599, USA
Justin M. Wolter
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Campus Box #7255, Chapel Hill, NC 27599, USA; Department of Genetics, The University of North Carolina at Chapel Hill, Campus Box #7264, Chapel Hill, NC 27599, USA
Eric S. McCoy
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Smita R. Paranjape
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Bonnie Taylor-Blake
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Mark J. Zylka
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Campus Box #7255, Chapel Hill, NC 27599, USA; Corresponding author
Summary: The E3 ubiquitin ligase Ube3a is biallelically expressed in neural progenitors and glial cells, suggesting that UBE3A gain-of-function mutations might cause neurodevelopmental disorders irrespective of parent of origin. Here, we engineered a mouse line that harbors an autism-linked UBE3AT485A (T503A in mouse) gain-of-function mutation and evaluated phenotypes in animals that inherited the mutant allele paternally, maternally, or from both parents. We find that paternally and maternally expressed UBE3AT503A results in elevated UBE3A activity in neural progenitors and glial cells. Expression of UBE3AT503A from the maternal allele, but not the paternal one, leads to a persistent elevation of UBE3A activity in neurons. Mutant mice display behavioral phenotypes that differ by parent of origin. Expression of UBE3AT503A, irrespective of its parent of origin, promotes transient embryonic expansion of Zcchc12 lineage interneurons. Phenotypes of Ube3aT503A mice are distinct from Angelman syndrome model mice. Our study has clinical implications for a growing number of disease-linked UBE3A gain-of-function mutations.
