Differential localization of CRMP5 in cancer cells compared to normal condition

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Role of Adult-Born Versus Preexisting Neurons Born at P0 in Olfactory Perception in a Complex Olfactory Environment in Mice

International audienceOlfactory perceptual learning is defined as an improvement in the discrimination of perceptually close odorants after passive exposure to these odorants. In mice, simple olfactory perceptual learning involving the discrimination of two odorants depends on an increased number of adult-born neurons in the olfactory bulb, which refines the bulbar output. However, the olfactory environment is complex, raising the question of the adjustment of the bulbar network to multiple discrimination challenges. Perceptual learning of 1 to 6 pairs of similar odorants led to discrimination of all learned odor pairs. Increasing complexity did not increase adult-born neuron survival but enhanced the number of adult-born neurons responding to learned odorants and their spine density. Moreover, only complex learning induced morphological changes in neurons of the granule cell layer born during the first day of life (P0). Selective optogenetic inactivation of either population confirmed functional involvement of adult-born neurons regardless of the enrichment complexity, while preexisting neurons were required for complex discrimination only

Role of Adult-Born Versus Preexisting Neurons Born at P0 in Olfactory Perception in a Complex Olfactory Environment in Mice

International audienceOlfactory perceptual learning is defined as an improvement in the discrimination of perceptually close odorants after passive exposure to these odorants. In mice, simple olfactory perceptual learning involving the discrimination of two odorants depends on an increased number of adult-born neurons in the olfactory bulb, which refines the bulbar output. However, the olfactory environment is complex, raising the question of the adjustment of the bulbar network to multiple discrimination challenges. Perceptual learning of 1 to 6 pairs of similar odorants led to discrimination of all learned odor pairs. Increasing complexity did not increase adult-born neuron survival but enhanced the number of adult-born neurons responding to learned odorants and their spine density. Moreover, only complex learning induced morphological changes in neurons of the granule cell layer born during the first day of life (P0). Selective optogenetic inactivation of either population confirmed functional involvement of adult-born neurons regardless of the enrichment complexity, while preexisting neurons were required for complex discrimination only

Identification of a new CRMP5 isoform present in the nucleus of cancer cells and enhancing their proliferation

International audienceCollapsin Response Mediator Protein 5 (CRMP5) belongs to a family of five cytosolic proteins highly expressed in the developing nervous system but downregulated in the adult brain. When expressed at the adult stage, CRMP5 is involved in neurological disorders. Indeed, CRMP5 is found expressed in cancer cells of some brain tumors, such as glioblastoma, or in small cell lung cancer causing paraneoplastic neurological syndromes as a result of cancer-induced auto-immune processes. Nevertheless, its role in cancer pathology is still obscure. Here, we show a new short isoform, derived from C-terminal processing of CRMP5, presenting a nuclear localization both in human glioblastoma, and in cancer cell lines (H69, GL15). By mutational analysis, we demonstrate that nuclear translocation occurs via nuclear localization signal (NLS), where the essential residue for nuclear location is K391. Direct CRMP5/ tubulin interaction, previously shown during brain development, does not occur for cytosolic CRMP5 in pathological conditions, leading to the suggestion that in cancer cells CRMP5 is not sequestered in the cytosol; therefore it may undergo C-terminal truncation allowing the exposure of the NLS for active translocation. Moreover, we show that the function associated with the CRMP5 nuclear targeting is an increase of cell proliferation activity

Role of Adult-Born Versus Preexisting Neurons Born at P0 in Olfactory Perception in a Complex Olfactory Environment in Mice

International audienceOlfactory perceptual learning is defined as an improvement in the discrimination of perceptually close odorants after passive exposure to these odorants. In mice, simple olfactory perceptual learning involving the discrimination of two odorants depends on an increased number of adult-born neurons in the olfactory bulb, which refines the bulbar output. However, the olfactory environment is complex, raising the question of the adjustment of the bulbar network to multiple discrimination challenges. Perceptual learning of 1 to 6 pairs of similar odorants led to discrimination of all learned odor pairs. Increasing complexity did not increase adult-born neuron survival but enhanced the number of adult-born neurons responding to learned odorants and their spine density. Moreover, only complex learning induced morphological changes in neurons of the granule cell layer born during the first day of life (P0). Selective optogenetic inactivation of either population confirmed functional involvement of adult-born neurons regardless of the enrichment complexity, while preexisting neurons were required for complex discrimination only

Transcriptional regulation of CRMP5 controls neurite outgrowth through Sox5

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Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene

International audienceBiallelic variants in RNU4ATAC, a non-coding gene transcribed into the minor spliceosome component U4atac snRNA, are responsible for three rare recessive developmental diseases, namely Taybi-Linder/MOPD1, Roifman and Lowry-Wood syndromes. Next-generation sequencing of clinically heterogeneous cohorts (children with either a suspected genetic disorder or a congenital microcephaly) recently identified mutations in this gene, illustrating how profoundly these technologies are modifying genetic testing and assessment. As RNU4ATAC has a single non-coding exon, the bioinformatic prediction algorithms assessing the effect of sequence variants on splicing or protein function are irrelevant, which makes variant interpretation challenging to molecular diagnostic laboratories. In order to facilitate and improve clinical diagnostic assessment and genetic counseling, we present i) an update of the previously reported RNU4ATAC mutations and an analysis of the genetic variations affecting this gene using the Genome Aggregation Database (gnomAD) resource; ii) the pathogenicity prediction performances of scores computed based on an RNA structure prediction tool and of those produced by the Combined Annotation Dependent Depletion tool for the 285 RNU4ATAC variants identified in patients or in large-scale sequencing projects; iii) a method, based on a cellular assay, that allows to measure the effect of RNU4ATAC variants on splicing efficiency of a minor (U12-type) reporter intron. Lastly, the concordance of bioinformatic predictions and cellular assay results was investigated

ERRα expression in bone metastases leads to an exacerbated anti-tumor immune response

International audienceBone is the most common metastatic site for breast cancer. Although the estrogen-related receptor alpha (ERRα) has been implicated in breast cancer cell dissemination to the bone from the primary tumor, its role after tumor cell anchorage in the bone microenvironment remains elusive. Here, we reveal that ERRα inhibits the progression of bone metastases of breast cancer cells by increasing the immune activity of the bone microenvironment. Overexpression of ERRα in breast cancer bone metastases induced expression of chemokines CCL17 and CCL20 and repressed production of TGFβ3. Subsequently, CD8(+) T lymphocytes recruited to bone metastases escaped TGFβ signaling control and were endowed with exacerbated cytotoxic features, resulting in significant reduction in metastases. The clinical relevance of our findings in mice was confirmed in over 240 patients with breast cancer. Thus, this study reveals that ERRα regulates immune properties in the bone microenvironment that contributes to decreasing metastatic growth. SIGNIFICANCE: This study places ERRα at the interplay between the immune response and bone metastases of breast cancer, highlighting a potential target for intervention in advanced disease