Ankrd11 is a chromatin regulator involved in autism that is essential for neural development

Dev Cell. 2015 Jan 12;32(1):31-42. doi: 10.1016/j.devcel.2014.11.031.

Denis Gallagher ¹, Anastassia Voronova ², Mark A Zander ², Gonzalo I Cancino ², Alexa Bramall ², Matthew P Krause ², Clemer Abad ³, Mustafa Tekin ³, Paul M Neilsen ⁴, David F Callen ⁵, Stephen W Scherer ⁶, Gordon M Keller ⁷, David R Kaplan ⁸, Katherina Walz ³, Freda D Miller ⁹

Affiliations

1 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.
2 Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
3 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.
4 Swinburne University of Technology, Sarawak Campus, Kuching 93350, Sarawak, Malaysia.
5 Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide SA 5000, Australia.
6 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.
7 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.
8 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.
9 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.

PMID: 25556659 DOI: 10.1016/j.devcel.2014.11.031

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.

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