CECR2, a protein involved in neurulation, forms a novel chromatin remodeling complex with SNF2L

Abstract

Chromatin remodeling complexes play critical roles in development. Here we describe a transcription factor, CECR2, which is involved in neurulation and chromatin remodeling. CECR2 shows complex alternative splicing, but all variants contain DDT and bromodomain motifs. A mutant mouse line was generated from an embryonic stem cell line containing a genetrap within Cecr2. Reporter gene expression demonstrated Cecr2 expression to be predominantly neural in the embryo. Mice homozygous for the Cecr2 genetrap-induced mutation show a high penetrance of the neural tube defect exencephaly, the human equivalent of anencephaly, in a strain-dependent fashion. Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation.

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

“…Both Cecr2 Gt45Bic and Cecr2 tm1.1Hemc homozygous mutants show defects in the orientation of the stereocilia bundles and the organization of the hair cell rows. In addition, we have previously shown that Cecr2 mutants have NTDs (exencephaly) and open eyelids (Banting et al, 2005). This combination of defects lead us to examine whether the PCP pathway was being affected by the loss of Cecr2.…”

“…background (Banting et al, 2005). The collection of Cecr2 Gt45Bic embryos for inner ear analysis produced 1/73 exencephalic heterozygotes (1.3%).…”

“…Xgal staining at 13.5 days post coitus (dpc) previously showed that Cecr2 is expressed in the nervous system (brain, spinal cord, spinal ganglia, and forming retina), as well as the nasal epithelium, lens, limb, and intercostal mesenchyme (Banting et al, 2005). Whole-mount embryos at 9.5 dpc showed Xgal staining along the closed neural tube.…”

“…Two different Cecr2 mutations have been reported. A hypomorphic genetrap mutation (Cecr2 Gt45Bic ) develops exencephaly with 74% penetrance on a BALB/c genetic background (Banting et al, 2005). Open eyelids are present in most mutants.…”

“…CECR2 is a chromatin remodeling protein that forms the CERF complex with SNF2L/SMARCA1 (Banting et al, 2005). The specific role of the CERF complex in neurulation is not known.…”