Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model

The Journal of Clinical Investigation
Sara Silva-SantosYpe Elgersma

Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal Ube3a allele and determined that there are distinct neurodevelopmental windows during which Ube3a restoration can rescue AS-relevant phenotypes. Motor deficits were rescued by Ube3a reinstatement in adolescent mice, whereas anxiety, repetitive behavior, and epilepsy were only rescued when Ube3a was reinstated during early development. In contrast, hippocampal synaptic plasticity could be restored at any age. Together, these findings suggest th...Continue Reading

References

Aug 18, 1997·Biochemical and Biophysical Research Communications·K Sakai, J i Miyazaki
Jan 26, 2005·Brain & Development·Charles Williams
Feb 18, 2006·Proceedings of the National Academy of Sciences of the United States of America·Hiroko KoikeJoseph A Gogos
May 8, 2007·Neuron·Steven J ClapcoteJohn C Roder
May 20, 2011·Trends in Neurosciences·Angela M MabbBenjamin D Philpot
Dec 23, 2011·Nature·Arthur L Beaudet
Dec 23, 2011·Nature·Hsien-Sung HuangBenjamin D Philpot
Apr 3, 2012·Annual Review of Neuroscience·Christiaan N Levelt, Mark Hübener
Apr 17, 2012·Neuron·Aditi Bhattacharya, Eric Klann
May 1, 2012·Trends in Neurosciences·Rhiannon M MeredithIoannis Kramvis
Jan 9, 2013·Behavioural Brain Research·Hsien-Sung HuangSheryl S Moy
Apr 26, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Alan D WorkmanBarbara L Finlay
Sep 3, 2014·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Deepika SuriMark S Ansorge

Citations

Nov 13, 2015·Expert Opinion on Therapeutic Targets·Xiaoning BiMichel Baudry
Oct 18, 2015·Human Molecular Genetics·Caroline F BruinsmaYpe Elgersma
Nov 21, 2015·Epigenomics·Janine M LaSalleStormy J Chamberlain
Oct 7, 2015·Frontiers in Neuroscience·Gabrielle L Sell, Seth S Margolis
Jul 28, 2016·Biological Psychiatry·Eunee LeeEunjoon Kim
Sep 13, 2016·Nature Reviews. Neurology·Karin BuitingBernhard Horsthemke
Oct 16, 2016·Prenatal Diagnosis·Jiani Yin, Christian P Schaaf
Apr 12, 2017·Neurochemical Research·James P ReynoldsDavid C Henshall
Dec 9, 2017·Nature Reviews. Drug Discovery·Elizabeth M Berry-KravisSébastien Jacquemont
Apr 6, 2018·International Journal of Molecular Sciences·Sara GuzzettiSilvia Russo
Oct 4, 2015·Nature·Ype Elgersma
Oct 24, 2018·The Journal of Clinical Investigation·Bin GuBenjamin D Philpot
Jan 29, 2019·Human Molecular Genetics·Ryohei FurumaiToru Takumi
Sep 11, 2019·The Journal of Clinical Investigation·Bin GuBenjamin D Philpot
Sep 7, 2019·Autism Research : Official Journal of the International Society for Autism Research·Mark J Zylka
Jun 21, 2019·Neurology·Iris OverwaterENCORE Expertise Centre for Neurodevelopmental Disorders
Feb 23, 2020·The FEBS Journal·Carina MarangaSimão Teixeira da Rocha
Dec 24, 2019·Journal of Neuroscience Research·Xin Yang
May 26, 2020·American Journal of Medical Genetics. Part a·Dawn AdamsHelen Heussler
Jul 16, 2020·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Veronica B Searles QuickMatthew W State
Oct 21, 2015·The Journal of Clinical Investigation·Caroline F BruinsmaYpe Elgersma
Nov 20, 2016·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Wen-Hann Tan, Lynne M Bird
Mar 23, 2017·Frontiers in Cellular Neuroscience·Masaaki Sato
Jan 29, 2019·Frontiers in Molecular Neuroscience·Simon Jesse LopezJanine M LaSalle
May 4, 2020·Journal of Neurodevelopmental Disorders·Khaleel A RazakCraig A Erickson
May 28, 2020·Journal of Clinical Medicine·Lilach SimchiHanoch Kaphzan
Sep 29, 2020·Neural Regeneration Research·Gilad Levy, Boaz Barak
Aug 21, 2020·Learning & Memory·Maria N Schultz, Jacqueline N Crawley
Jan 23, 2018·Frontiers in Cellular Neuroscience·Tiantian WangJ Gerard G Borst
May 31, 2019·Molecular Autism·Monica SonzogniYpe Elgersma
Sep 4, 2020·Journal of Neurochemistry·Thomas J TurnerGabriele Lignani
Mar 2, 2018·Frontiers in Genetics·Arlene J GeorgeAngela M Mabb
Jun 29, 2018·Molecular Autism·Matthew BengerNicholas D Mazarakis
May 9, 2020·AJNR. American Journal of Neuroradiology·H M YoonM S Yum
Dec 19, 2019·Frontiers in Molecular Neuroscience·Vipendra KumarNihar Ranjan Jana
Jun 6, 2017·Frontiers in Molecular Neuroscience·Arun UpadhyayAmit Mishra
Aug 9, 2020·Frontiers in Neuroanatomy·Hyojin KimBenjamin D Philpot
Apr 23, 2020·Cells·Linn Amanda SydingRadislav Sedlacek
Oct 28, 2020·Autism Research : Official Journal of the International Society for Autism Research·Emmanuel CruzCristina M Alberini
Aug 29, 2020·Neuroscience and Biobehavioral Reviews·Sehrish JavedWei-Hsiang Huang

Related Concepts

Ube3a protein, mouse
Age Factors
Metazoa
Nervousness
Cerebellum
Insula of Reil
Single Seizure
Synthetic Genes
Structure of Subiculum Hippocampi
Etat Marbre

Related Feeds

Angelman Syndrome

Angelman syndrome is a neurogenetic imprinting disorder caused by loss of the maternally inherited UBE3A gene and is characterized by generalized epilepsy, limited expressive speech, sleep dysfunction, and movement disorders. Here is the latest research.

Anxiety Disorders

Discover the latest research on anxiety disorders including agoraphobia, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder here.