Brain and neural tube defects are among the most common human congenital malformations. One prominent example is the Chiari malformation (CM), a developmental defect characterized by abnormal growth of the brainstem and cerebellar herniation. CMs can be asymptomatic or can cause a wide range of clinical conditions. Malformations may, for instance, cause severe neural tube defects and hydrocephalus, in turn leading to incapacitating or lethal conditions. CMs and most other congenital brain defects have a pronounced genetic basis and a complex inheritance pattern. The genetic causes of these defects, and the molecular interplay between known environmental risk factors (for example, folic acid deficiency) and susceptibility genes are currently ill defined.
In this study, the authors identify two genetic factors that cause Chiari-like malformations in mice. One of these genes, Suz12, is a member of a polycomb complex, a group of proteins that act as epigenetic regulators of gene expression. In comparison to normal, wild-type mice, which have two copies of Suz12, mice with only one copy of Suz12 have brain and neural tube defects. Some of the Suz12 heterozygotes show cerebellar herniation and an enlarged brainstem accompanied by occipital cortical alterations and spina bifida, almost perfectly resembling CM as seen in some human patients. The most impaired mice have downward displacement of the cerebellum, which causes hydrocephalus. The authors also demonstrate that Zac1 (also known as Plagl1 or Lot1), a regulator of neuronal proliferation, is part of the same molecular pathway affected by Suz12 deficiency.
Polycomb proteins are starting to be recognized as having a key role in human disease; this study demonstrates that polycomb protein complexes can play a role in nervous system malformations as well. This work strongly suggests that developmental brain abnormalities such as CMs can result from altered epigenetic regulation of genes involved in cell proliferation in the brain.