Snf2I Regulates Foxg1-Dependent Progenitor Cell Expansion in the Developing Brain

Regenerative Medicine Program, Ottawa Hospital Research Institute, and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada.
Developmental Cell (Impact Factor: 9.71). 04/2012; 22(4):871-8. DOI: 10.1016/j.devcel.2012.01.020
Source: PubMed

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.

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Available from: Michael A Rudnicki, Jan 23, 2014
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    • "Other studies suggest that the inhibition of SNF2L expression selectively leads to DNA damage, growth inhibition, and cancer cell death.10 Snf2l mutant mice exhibit forebrain hypercellularity arising from increased Foxg1 expression, increased progenitor-cell expansion, and delayed differentiation.11 Recent studies indicate that SNF2L is broadly expressed in primary human tissues and suppresses cell proliferation and migration and attenuates Wnt signaling.12 "
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    ABSTRACT: Purpose SNF2L belongs to Imitation Switch family and plays an essential role in neural tissues and gonads. In our previous studies, we have demonstrated that the basal transcription of human SNF2L gene is regulated by two cis-elements, cAMP response element (CRE)- and Sp1-binding sites. Recent studies suggested that cyclic adenosine monophosphate (cAMP) stimulation significantly up-regulated SNF2L expression in ovarian granulose cells. These data suggested that protein kinase-mediated signal pathways might also regulate SNF2L expression in neural cells. We therefore investigated the effects of agents that activate protein kinases A on SNF2L gene expression in neural cells. Materials and Methods To increase intracellular cAMP levels, all neural cells were treated with forskolin and dbcAMP, two cAMP response activators. We exmined the effects of cAMP on the promoter activity of human SNF2L gene by luciferase reporter gene assays, and further examined the effects of cAMP on endogenous SNF2L mRNA levels by qPCR. Results Transient expression of a luciferase fusion gene under the control of the SNF2L promoter was significantly increased by treatment of rat primary neurons with forskolin or dbcAMP, but not PC12, C6 and SH-SY5Y cells. Consistently, treatment with forskolin or dbcAMP could enhance endogenous SNF2L mRNA levels also only in rat primary neurons. Conclusion These results suggest that the CRE consensus sequence in the SNF2L proximal promoter most likely confers constitutive activation and regulation by cAMP in neural cells.
    Yonsei medical journal 05/2013; 54(3):772-7. DOI:10.3349/ymj.2013.54.3.772 · 1.29 Impact Factor
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    Epigenetics & Chromatin 04/2013; 6(1). DOI:10.1186/1756-8935-6-S1-P105 · 5.33 Impact Factor
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    ABSTRACT: Imitation Switch (ISWI) proteins are catalytic subunits of chromatin remodeling complexes that alter nucleosome positioning by hydrolyzing ATP to regulate access to DNA. In mice there are two paralogs, SNF2-homolog (SNF2H) and SNF2-like (SNF2L), which participate in different complexes and have contrasting patterns of expression. Here we investigate the role of SNF2L in ovaries by characterizing a mouse bearing an inactivating deletion of exon 6 which disrupts the ATPase domain. Snf2l mutant mice produce significantly fewer eggs than control mice when superovulated. Gonadotropin stimulation leads to a significant deficit in secondary follicles and an increase in abnormal antral follicles. Mutant females also fail to induce Fibrinogen-like 2 (Fgl2) in response to human chorionic gonadotropin (hCG), while overexpression of SNF2L is sufficient to drive its expression in granulosa cells. SNF2L is also shown to directly interact with the nuclear receptor co-activator Flightless I (FLI-I) as shown by immunoprecipitation. These results begin to establish a role for SNF2L in the precise coordination of gene expression in granulosa cells during folliculogenesis, and its broader implications in fertility.
    Biology of Reproduction 04/2013; 88(6). DOI:10.1095/biolreprod.112.105742 · 3.32 Impact Factor
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