RT Journal Article SR Electronic T1 Haploinsufficiency of the murine polycomb gene Suz12 results in diverse malformations of the brain and neural tube JF Disease Models & Mechanisms JO Dis Models Mech FD The Company of Biologists Limited SP 412 OP 418 DO 10.1242/dmm.001602 VO 2 IS 7-8 A1 Miró, Xavier A1 Zhou, Xunlei A1 Boretius, Susann A1 Michaelis, Thomas A1 Kubisch, Christian A1 Alvarez-Bolado, Gonzalo A1 Gruss, Peter YR 2009 UL http://dmm.biologists.org/content/2/7-8/412.abstract AB Polycomb proteins are epigenetic regulators of gene expression. Human central nervous system (CNS) malformations are congenital defects of the brain and spinal cord. One example of a human CNS malformation is Chiari malformation (CM), which presents as abnormal brainstem growth and cerebellar herniation, sometimes accompanied by spina bifida and cortical defects; it can occur in families. Clinically, CM ranges from an asymptomatic condition to one with incapacitating or lethal symptoms, including neural tube defects and hydrocephalus. However, no genes that are causally involved in any manifestation of CM or similar malformations have been identified. Here, we show that a pathway that involves Zac1 (also known as Plagl1 or Lot1) and controls neuronal proliferation is altered in mice that are heterozygous for the polycomb gene Suz12, resulting in a phenotype that overlaps with some clinical manifestations of the CM spectrum. Suz12 heterozygotes show cerebellar herniation and an enlarged brainstem, accompanied by occipital cortical alterations and spina bifida. Downward displacement of the cerebellum causes hydrocephalus in the most severely impaired cases. Although the involvement of polycomb genes in human disease is starting to be recognized, this is the first demonstration of their role in nervous system malformations. Our work strongly suggests that brain malformations such as CM can result from altered epigenetic regulation of genes involved in cell proliferation in the brain.