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

Department of Biological Sciences, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
Human Molecular Genetics (Impact Factor: 6.68). 03/2005; 14(4):513-24. DOI: 10.1093/hmg/ddi048
Source: PubMed

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.

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Available from: Heather E McDermid, Jul 21, 2015
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    • "Other studies highlight a more global role for ISWI in chromatin compaction (Corona et al., 2007; Li et al., 2010). The Snf2l protein is part of two different complexes, CERF (Banting et al., 2005) and NURF (Barak et al., 2003), but which one regulates Foxg1 expression is unclear. The NURF complex is largely considered an activator of gene expression, whereas the function of the CERF complex remains unknown (Lazzaro et al., 2006; Wysocka et al., 2006). "
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    ABSTRACT: Balancing progenitor cell self-renewal and differentiation is essential for brain development and is regulated by the activity of chromatin remodeling complexes. Nevertheless, linking chromatin changes to specific pathways that control cortical histogenesis remains a challenge. Here we identify a genetic interaction between the chromatin remodeler Snf2l and Foxg1, a key regulator of neurogenesis. Snf2l mutant mice exhibit forebrain hypercellularity arising from increased Foxg1 expression, increased progenitor cell expansion, and delayed differentiation. We demonstrate that Snf2l binds to the Foxg1 locus at midneurogenesis and that the phenotype is rescued by reducing Foxg1 dosage, thus revealing that Snf2l and Foxg1 function antagonistically to regulate brain size.
    Developmental Cell 04/2012; 22(4):871-8. DOI:10.1016/j.devcel.2012.01.020 · 10.37 Impact Factor
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    • "During Neurulation Cecr2 Is Expressed in Both the Neural Epithelium and Head Mesenchyme To better understand the role of Cecr2 during neurulation, we examined its expression during this time using the LacZ fusion protein of the Cecr2 Gt45Bic mutation. 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. "
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    ABSTRACT: The loss of Cecr2, which encodes a chromatin remodeling protein, has been associated with the neural tube defect (NTD) exencephaly and open eyelids in mice. Here, we show that two independent mutations of Cecr2 are also associated with specific inner ear defects. Homozygous mutant 18.5 days post coitus (dpc) fetuses exhibited smaller cochleae as well as rotational defects of sensory cells and extra cell rows in the inner ear reminiscent of planar cell polarity (PCP) mutants. Cecr2 was expressed in the neuroepithelium, head mesenchyme, and the cochlear floor. Although limited genetic interaction for NTDs was seen with Vangl2, a microarray analysis of PCP genes did not reveal a direct connection to this pathway. The mechanism of Cecr2 action in neurogenesis and inner ear development is likely complex.
    Developmental Dynamics 02/2011; 240(2):372-83. DOI:10.1002/dvdy.22547 · 2.67 Impact Factor
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    • "Mice harboring mutations in other Swi/Snf type complexes, including Brg1 (Bultman et al., 2000),. Srg3, and CECR2 (Banting et al., 2005), also exhibit NTDs, indicating that multiple ATP-dependent chromatin remodeling complexes are involved in neural development. Specific HATs and their binding proteins are also essential for this process. "
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    ABSTRACT: Histone acetyltransferases (HATs) are important to gene activation, altering chromatin structures to facilitate association of transcription proteins with gene promoters. The functions of individual HATs in mammalian developmental are not well defined. Our previous studies demonstrated that Gcn5, a prototypical HAT, is required for mesodermal maintenance in early embryos. Homozygous Gcn5 null embryos die soon after gastrulation, preventing determination of Gcn5 functions later during development. We report here the creation of a Gcn5(flox(neo)) allele, which is only partially functional and gives rise to a hypomorphic phenotype. Mice homozygous for this allele had an increased risk of cranial neural tube closure defects (NTDs) and exencephaly. These defects were found at an even greater penetrance in Gcn5(flox(neo)/Delta) embryos. These results indicate that normal levels of Gcn5 expression are critical for neural tube closure in mice and predict that mutations in this HAT may be associated with increased risk of NTDs in humans.
    Developmental Dynamics 04/2008; 237(4):928-40. DOI:10.1002/dvdy.21479 · 2.67 Impact Factor
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