Cerebellar gene expression profiles of mouse models for Rett syndrome reveal novel MeCP2 targets

<p>Abstract</p> <p>Background</p> <p>MeCP2, methyl-CpG-binding protein 2, binds to methylated cytosines at CpG dinucleotides, as well as to unmethylated DNA, and affects chromatin condensation. <it>MECP2 </it>mutations in females lead to Rett syndrome, a neurological disorder characterized by developmental stagnation and regression, loss of purposeful hand movements and speech, stereotypic hand movements, deceleration of brain growth, autonomic dysfunction and seizures. Most mutations occur <it>de novo </it>during spermatogenesis. Located at Xq28, <it>MECP2 </it>is subject to X inactivation, and affected females are mosaic. Rare hemizygous males suffer from a severe congenital encephalopathy.</p> <p>Methods</p> <p>To identify the pathways mis-regulated by MeCP2 deficiency, microarray-based global gene expression studies were carried out in cerebellum of <it>Mecp2 </it>mutant mice. We compared transcript levels in mutant/wildtype male sibs of two different MeCP2-deficient mouse models at 2, 4 and 8 weeks of age. Increased transcript levels were evaluated by real-time quantitative RT-PCR. Chromatin immunoprecipitation assays were used to document <it>in vivo </it>MeCP2 binding to promoter regions of candidate target genes.</p> <p>Results</p> <p>Of several hundred genes with altered expression levels in the mutants, twice as many were increased than decreased, and only 27 were differentially expressed at more than one time point. The number of misregulated genes was 30% lower in mice with the exon 3 deletion (<it>Mecp2</it>^tm1.1Jae) than in mice with the larger deletion (<it>Mecp2</it>^tm1.1Bird). Between the mutants, few genes overlapped at each time point. Real-time quantitative RT-PCR assays validated increased transcript levels for four genes: <it>Irak1</it>, interleukin-1 receptor-associated kinase 1; <it>Fxyd1</it>, phospholemman, associated with Na, K-ATPase;<it>Reln</it>, encoding an extracellular signaling molecule essential for neuronal lamination and synaptic plasticity; and <it>Gtl2/Meg3</it>, an imprinted maternally expressed non-translated RNA that serves as a host gene for C/D box snoRNAs and microRNAs. Chromatin immunoprecipitation assays documented <it>in vivo </it>MeCP2 binding to promoter regions of <it>Fxyd1, Reln</it>, and <it>Gtl2</it>.</p> <p>Conclusion</p> <p>Transcriptional profiling of cerebellum failed to detect significant global changes in <it>Mecp2</it>-mutant mice. Increased transcript levels of <it>Irak1, Fxyd1, Reln</it>, and <it>Gtl2 </it>may contribute to the neuronal dysfunction in MeCP2-deficient mice and individuals with Rett syndrome. Our data provide testable hypotheses for future studies of the regulatory or signaling pathways that these genes act on.</p

Spatiotemporal dynamics of the agricultural landscape mosaic drives distribution and abundance of dominant carabid beetles

International audienceContext Agroecosystems are dynamic, with yearly changing proportions of crops. Explicit consideration of this temporal heterogeneity is required to decipher population and community patterns but remains poorly studied. Objectives We evaluated the impact on the activity-density of two dominant carabid species (Poecilus cupreus and Anchomenus dorsalis) of (1) local crop, current year landscape composition, and their interaction, and (2) inter-annual changes in landscape composition due to crop rotations. Methods Carabids were sampled using pitfall-traps in 188 fields of winter cereals and oilseed rape in three agricultural areas of western France contrasting in their spatial heterogeneity. We summarized landscape composition in the current and previous years in a multi-scale perspective, using buffers of increasing size around sampling locations. Results Both species were more abundant in oilseed rape, and in landscapes with a higher proportion of oilseed rape in the previous year. P. cupreus abundance was negatively influenced by oilseed rape proportion in the current year landscape in winter cereals and positively by winter cereal proportion in oilseed rape. A. dorsalis was globally impacted at finer scales than P. cupreus. Conclusions Resource concentration and dilution-concentration processes jointly appear to cause transient dynamics of population abundance and distribution among habitat patches. Inter-patch movements across years appear to be key drivers of carabids’ survival and distribution, in response to crop rotation. Therefore, the explicit consideration of the spatiotemporal dynamics of landscape composition can allow future studies to better evidence ecological processes behind observed species patterns and help developing new management strategies