Impaired KDM2B-mediated PRC1 recruitment to chromatin causes defective neural stem cell self-renewal and ASD/ID-like behaviors
Yuen Gao,
Natalia Duque-Wilckens,
Mohammad B. Aljazi,
Adam J. Moeser,
George I. Mias,
Alfred J. Robison,
Yi Zhang,
Jin He
Affiliations
Yuen Gao
Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, MI, USA
Natalia Duque-Wilckens
Department of Physiology, College of Natural Science, Michigan State University, East Lansing, MI, USA; Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, East Lansing, MI, USA
Mohammad B. Aljazi
Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, MI, USA
Adam J. Moeser
Department of Physiology, College of Natural Science, Michigan State University, East Lansing, MI, USA; Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, East Lansing, MI, USA
George I. Mias
Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, MI, USA; Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA
Alfred J. Robison
Department of Physiology, College of Natural Science, Michigan State University, East Lansing, MI, USA
Yi Zhang
Howard Hughes Medical Institute, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, USA; Department of Genetics, Harvard University, Boston, MA, USA; Harvard Stem Cell Institute WAB-149G, Boston, MA, USA; Corresponding author
Jin He
Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, MI, USA; Corresponding author
Summary: Recent clinical studies report that chromosomal 12q24.31 microdeletions are associated with autism spectrum disorder (ASD) and intellectual disability (ID). However, the causality and underlying mechanisms linking 12q24.31 microdeletions to ASD/ID remain undetermined. Here we show Kdm2b, one gene located in chromosomal 12q24.31, plays a critical role in maintaining neural stem cells (NSCs) in the mouse brain. Loss of the CxxC-ZF domain of KDM2B impairs its function in recruiting Polycomb repressive complex 1 (PRC1) to chromatin, resulting in de-repression of genes involved in cell apoptosis, cell-cycle arrest, NSC senescence, and loss of NSC populations in the brain. Of importance, the Kdm2b mutation is sufficient to induce ASD/ID-like behavioral and memory deficits. Thus, our study reveals a critical role of KDM2B in normal brain development, a causality between the Kdm2b mutation and ASD/ID-like phenotypes in mice, and potential molecular mechanisms linking the function of KDM2B-PRC1 in transcriptional regulation to the 12q24.31 microdeletion-associated ASD/ID.
