Regional and cellular organization of the autism-associated protein UBE3A/E6AP and its antisense transcript in the brain of the developing rhesus monkey.
Chavely Gonzalez Ramirez, Sarah G Salvador, Ridthi Kartik Rekha Patel, Sarah Clark, Noah W Miller, Lucas M James, Nicholas W Ringelberg, Jeremy M Simon, Jeffrey Bennett, David G Amaral, Alain C Burette, Benjamin D Philpot
Author Information
Chavely Gonzalez Ramirez: Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Sarah G Salvador: Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Ridthi Kartik Rekha Patel: Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Sarah Clark: Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Noah W Miller: Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Lucas M James: Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Nicholas W Ringelberg: Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Jeremy M Simon: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States.
Jeffrey Bennett: Department of Psychiatry and Behavioral Sciences, MIND Institute, Davis, CA, United States.
David G Amaral: Department of Psychiatry and Behavioral Sciences, MIND Institute, Davis, CA, United States.
Alain C Burette: Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Benjamin D Philpot: Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Angelman syndrome (AS) is a neurogenetic disorder caused by mutations or deletions in the maternally-inherited allele, leading to a loss of UBE3A protein expression in neurons. The paternally-inherited allele is epigenetically silenced in neurons during development by a noncoding transcript (). The absence of neuronal UBE3A results in severe neurological symptoms, including speech and language impairments, intellectual disability, and seizures. While no cure exists, therapies aiming to restore UBE3A function-either by gene addition or by targeting -are under development. Progress in developing these treatments relies heavily on inferences drawn from mouse studies about the function of UBE3A in the human brain. To aid translational efforts and to gain an understanding of UBE3A and biology with greater relevance to human neurodevelopmental contexts, we investigated UBE3A and expression in the developing brain of the rhesus macaque, a species that exhibits complex social behaviors, resembling aspects of human behavior to a greater degree than mice. Combining immunohistochemistry and hybridization, we mapped UBE3A and regional and cellular expression in normal prenatal, neonatal, and adolescent rhesus macaque brains. We show that key hallmarks of UBE3A biology, well-known in rodents, are also present in macaques, and suggest paternal silencing in neurons-but not glial cells-in the macaque brain, with onset between gestational day 48 and 100. These findings support proposals that early-life, perhaps even prenatal, intervention is optimal for overcoming the maternal allele loss of linked to AS.
