Fatty Acid Desaturation Links Germ Cell Loss to Longevity Through NHR-80/HNF4 in C. elegans

Lifespan extension induced by germline ablation in C. elegans is regulated by the nuclear hormone receptor NHR-80 in a process that requires the production of oleic acid by activation of the lipid desaturase FAT-6/SCD1

Impact de la lignée germinale sur le métabolisme lipidique chez Caenorhabditis elegans

Mon laboratoire d’accueil travaille sur la génétique du vieillissement. En particulier, nous étudions l’impact de la lignée germinale et de la restriction calorique sur la longévité. Un mutant ne possédant pas de lignée germinale (glp-1) à une durée de vie augmentée de 60% (Hsin & Kenyon, 1999), et présente un défaut de mobilisation des lipides en condition de jeûne.Mon sujet a consisté à mieux comprendre le lien entre la lignée germinale, le catabolisme lipidique et la longévité. Nous avons montré que le défaut de mobilisation des lipides chez le mutant glp-1 était dû à l’absence de production d’ovocytes. De plus, ce défaut de mobilisation des lipides est associé à une lipolyse altérée chez ces mutants. En effet, nous avons pu montrer que l’altération du métabolisme lipidique, en condition de jeûne, des animaux sans lignée germinale était liée à l’absence d’induction de deux lipases, lipl-5 et lipl-7. De plus, ces lipases sont régulées par NHR-80/HNF4 et DAF-16/FOXO, deux régulateurs importants de la longévité bien qu’elles ne soient pas impliquées directement dans le vieillissement.En résumé, nous avons montré que le défaut de mobilisation des lipides des mutants ne possédant pas de lignée germinale était dû à un défaut de lipolyse et que, dans ce contexte, le métabolisme lipidique et le vieillissement sont découplés.Ces deux phénotypes sont cependant liés par le partage de facteurs de transcription qui les régulent

Coelomocytes regulate starvation-induced fat catabolism and lifespan extension through the lipase LIPL-5 in Caenorhabditis elegans

International audienceDietary restriction is known to extend the lifespan and reduce fat stores in most species tested to date, but the molecular mechanisms linking these events remain unclear. Here, we found that bacterial deprivation of Caenorhabditis elegans leads to lifespan extension with concomitant mobilization of fat stores. We find that LIPL-5 expression is induced by starvation and that the LIPL-5 lipase is present in coelomocyte cells and regulates fat catabolism and longevity during the bacterial deprivation response. Either LIPL-5 or coelomocyte deficiency prevents the rapid mobilization of intestinal triacylglycerol and enhanced lifespan extension in response to bacterial deprivation, whereas the combination of both defects has no additional or synergistic effect. Thus, the capacity to mobilize fat via LIPL-5 is directly linked to an animal's capacity to withstand long-term nutrient deprivation. Our data establish a role for LIPL-5 and coelomocytes in regulating fat consumption and lifespan extension upon DR

Author Correction: DRP-1-mediated apoptosis induces muscle degeneration in dystrophin mutants

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Post-transcriptional regulation of transcription factor codes in immature neurons drives neuronal diversity

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The post-transcriptional regulation of TFs in immature motoneurons shapes the axon-muscle connectome

SUMMARY Temporal factors expressed sequentially in neural stem cells, such as RNA binding proteins (RBPs) or transcription factors (TFs), are key elements in the generation of neuronal diversity. The molecular mechanism underlying how the temporal identity of stem cells is decoded into their progeny to generate neuronal diversity is largely unknown. Here, we used genetic and new computational tools to study with precision the unique fates of the progeny of a stem cell producing 29 morphologically distinct leg motoneurons (MNs) in Drosophila . We identified 40 TFs expressed in this MN lineage, 15 of which are expressed in a combinatorial manner in immature MNs just before their morphological differentiation. By following TF expression patterns at an earlier developmental stages, we discovered 19 combinatorial codes of TFs that were progressively established in immature MNs as a function of their birth order. The comparison of the RNA and protein expression profiles of 6 TFs revealed that post-transcriptional regulation plays an essential role in shaping these TF codes. We found that the two known RBPs, Imp and Syp, expressed sequentially in neuronal stem cells, are upstream regulators of the TF codes. Both RBPs are key players in the construction of axon-muscle connectome through the post-transcriptional regulation of 5 of the 6 TFs examined. By deciphering the function of Imp in the immature MNs with respect to the stem cell of the same lineage, we propose a model where RBPs shape the morphological fates of MNs through post-transcriptional regulation of TF codes in immature MNs. Taken together, our study reveals that immature MNs are plastic cells that have the potential to acquire many morphological fates. The molecular basis of MN plasticity originates in the broad expression of different TF mRNA, that are post-transcriptionally shaped into TF codes by Imp and Syp, and potentially by other RBPs that remain to be discovered, to determine their morphological fates

Inhibition of Sox2 Expression in the Adult Neural Stem Cell Niche In Vivo by Monocationic-based siRNA Delivery

RNA interference (RNAi) is a major tool for basic and applied investigations. However, obtaining RNAi data that have physiological significance requires investigation of regulations and therapeutic strategies in appropriate in vivo settings. To examine in vivo gene regulation and protein function in the adult neural stem cell (NSC) niche, we optimized a new non-viral vector for delivery of siRNA into the subventricular zone (SVZ). This brain region contains the neural stem and progenitor cells populations that express the stem cell marker, SOX2. Temporally and spatially controlled Sox2 knockdown was achieved using the monocationic lipid vector, IC10. siRNA/IC10 complexes were stable over time and smaller (<40 nm) than jetSi complexes (≈400 nm). Immunocytochemistry showed that siRNA/IC10 complexes efficiently target both the progenitor and stem cell populations in the adult SVZ. Injection of the complexes into the lateral brain ventricle resulted in specific knockdown of Sox2 in the SVZ. Furthermore, IC10-mediated transient in vivo knockdown of Sox2-modulated expression of several genes implicated in NSC maintenance. Taken together, these data show that IC10 cationic lipid formulation can efficiently vectorize siRNA in a specific area of the adult mouse brain, achieving spatially and temporally defined loss of function

NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation

Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD+) synthesis, consistent with a potential role for the essential cofactor NAD+ in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene’s muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5′-diphosphate (ADP)–ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD+ and are involved in pleiotropic events, including inflammation. In the mdx mouse model of DMD, we observed significant reductions in muscle NAD+ levels, concurrent increases in PARP activity, and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ biosynthesis. Replenishing NAD+ stores with dietary nicotinamide riboside supplementation improved muscle function and heart pathology in mdx and mdx/Utr−/− mice and reversed pathology in Caenorhabditis elegans models of DMD. The effects of NAD+ repletion in mdx mice relied on the improvement in mitochondrial function and structural protein expression (α-dystrobrevin and δ-sarcoglycan) and on the reductions in general poly(ADP)-ribosylation, inflammation, and fibrosis. In combination, these studies suggest that the replenishment of NAD+ may benefit patients with muscular dystrophies or other neuromuscular degenerative conditions characterized by the PARP/NNMT gene expression signatures.836