title: Ankrd11 is a chromatin regulator involved in autism that is essential for neural development.
abstract: Ankrd11 is a potential chromatin regulator implicated in neural development and autism spectrum disorder (ASD) with no known function in the brain. Here, we show that knockdown of Ankrd11 in developing murine or human cortical neural precursors caused decreased proliferation, reduced neurogenesis, and aberrant neuronal positioning. Similar cellular phenotypes and aberrant ASD-like behaviors were observed in Yoda mice carrying a point mutation in the Ankrd11 HDAC-binding domain. Consistent with a role for Ankrd11 in histone acetylation, Ankrd11 was associated with chromatin and colocalized with HDAC3, and expression and histone acetylation of Ankrd11 target genes were altered in Yoda neural precursors. Moreover, the Ankrd11 knockdown-mediated decrease in precursor proliferation was rescued by inhibiting histone acetyltransferase activity or expressing HDAC3. Thus, Ankrd11 is a crucial chromatin regulator that controls histone acetylation and gene expression during neural development, thereby providing a likely explanation for its association with cognitive dysfunction and ASD.
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; McEwen Center for Regenerative Medicine, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Gallagher
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Anastassia
authors.initials: A
authors.lastname: Voronova
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zander
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Gonzalo I
authors.initials: GI
authors.lastname: Cancino
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Alexa
authors.initials: A
authors.lastname: Bramall
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Krause
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Clemer
authors.initials: C
authors.lastname: Abad
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.affiliation: Swinburne University of Technology, Sarawak Campus, Kuching 93350, Sarawak, Malaysia.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Neilsen
authors.affiliation: Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: David F
authors.initials: DF
authors.lastname: Callen
authors.affiliation: Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: McEwen Center for Regenerative Medicine, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1X5, Canada.
authors.forename: Gordon M
authors.initials: GM
authors.lastname: Keller
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada. Electronic address: dkaplan@sickkids.ca.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Katherina
authors.initials: K
authors.lastname: Walz
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; McEwen Center for Regenerative Medicine, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1X5, Canada. Electronic address: fredam@sickkids.ca.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
mesh_terms: D000107:Acetylation; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D055495:Neurogenesis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099186:Histone Deacetylase 3
chemical_list: D015415:Biomarkers; D002843:Chromatin; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C528115:Ankrd11 protein, mouse