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

doi:10.1016/j.celrep.2023.112706

Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice

Cell Rep. 2023 Jul 25;42(7):112706. doi: 10.1016/j.celrep.2023.112706. Epub 2023 Jun 28.

Authors

Lei Xing¹, Jeremy M Simon², Travis S Ptacek³, Jason J Yi⁴, Lipin Loo⁵, Hanqian Mao⁴, Justin M Wolter⁶, Eric S McCoy⁵, Smita R Paranjape⁵, Bonnie Taylor-Blake⁵, Mark J Zylka⁷

Affiliations

¹ UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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. Electronic address: zylka@med.unc.edu.

Abstract

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 UBE3A^T485A (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 UBE3A^T503A results in elevated UBE3A activity in neural progenitors and glial cells. Expression of UBE3A^T503A 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 UBE3A^T503A, irrespective of its parent of origin, promotes transient embryonic expansion of Zcchc12 lineage interneurons. Phenotypes of Ube3a^T503A 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.

Keywords: Angelman syndrome; CP: Neuroscience; UBE3A; autism; neurodevelopmental disorders; single-cell RNA-seq.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Angelman Syndrome*
Animals
Autistic Disorder* / genetics
Disease Models, Animal
Gain of Function Mutation
Interneurons / metabolism
Maternal Inheritance
Mice
Phenotype
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism

Substances

Ubiquitin-Protein Ligases
Ube3a protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding