No abstract

Activity-dependent protein synthesis at synapses is dysregulated in the Fragile X syndrome (FXS). This process contributes to dendritic spine dysmorphogenesis and synaptic dysfunction in FXS. Matrix Metalloproteinase 9 (MMP-9) is an enzyme involved in activitydependent reorganization of dendritic spine architecture and was shown to regulate spine morphology in a mouse model of FXS, the Fmr1 knock-out mice. Here we show that MMP-9 mRNA is part of the FMRP complex and colocalizes in dendrites. In the absence of FMRP MMP-9 mRNA translation is increased at synapses, suggesting that this mechanism contributes to the increased metalloproteinase level at synapses of Fmr1 knock-out mice. We propose that such a local effect can contribute to the aberrant dendritic spine morphology observed in the Fmr1 knock-out mice and in patients with FXS.

The pattern of dendritic branching, together with the density of synapses and receptor composition, defines the electrical properties of a neuron. The development of the dendritic arbor and its additional stabilization are highly orchestrated at the molecular level and are guided by intrinsic mechanisms and extracellular information. Although protein translation is known to contribute to these processes, the role of its local component has not been fully explored. For local translation, mRNAs are transported to dendrites in their dormant form as ribonucleoparticles (RNPs). We hypothesized that disturbing spatial mRNA distribution via RNP targeting may result in severe underdevelopment of the dendritic arbor. Zipcode binding protein 1 (ZBP1) controls ␤-actin mRNA transport and translation in dendrites. We showed that proper cellular levels of ZBP1, its ability to engage in mRNA binding, and Src-dependent release of mRNA cargo from ZBP1 are vital for dendritic arbor development in cultured rat hippocampal neurons. Moreover, ␤-actin overexpression significantly alleviated the effects of ZBP1 knockdown. These results suggest that ZBP1-dependent dendritic mRNA transport contributes to proper dendritic branching.

Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.