Browsing by Issue Date, starting with "2019"
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- The vertebrate tail: a gene playground for evolutionPublication . Mallo, MoisésThe tail of all vertebrates, regardless of size and anatomical detail, derive from a post-anal extension of the embryo known as the tail bud. Formation, growth and differentiation of this structure are closely associated with the activity of a group of cells that derive from the axial progenitors that build the spinal cord and the muscle-skeletal case of the trunk. Gdf11 activity switches the development of these progenitors from a trunk to a tail bud mode by changing the regulatory network that controls their growth and differentiation potential. Recent work in the mouse indicates that the tail bud regulatory network relies on the interconnected activities of the Lin28/let-7 axis and the Hox13 genes. As this network is likely to be conserved in other mammals, it is possible that the final length and anatomical composition of the adult tail result from the balance between the progenitor-promoting and -repressing activities provided by those genes. This balance might also determine the functional characteristics of the adult tail. Particularly relevant is its regeneration potential, intimately linked to the spinal cord. In mammals, known for their complete inability to regenerate the tail, the spinal cord is removed from the embryonic tail at late stages of development through a Hox13-dependent mechanism. In contrast, the tail of salamanders and lizards keep a functional spinal cord that actively guides the tail's regeneration process. I will argue that the distinct molecular networks controlling tail bud development provided a collection of readily accessible gene networks that were co-opted and combined during evolution either to end the active life of those progenitors or to make them generate the wide diversity of tail shapes and sizes observed among vertebrates.
- Beyond multiregional and simple out-of-Africa models of human evolutionPublication . Scerri, Eleanor M. L.; Chikhi, Lounès; Thomas, Mark G.
- iRhom2 and TNF: Partners or enemies?Publication . Badenes, Marina; Adrain, ColiniRhom2 is an essential cofactor for ADAM17, the metalloprotease that sheds both the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and TNF receptors (TNFRs) from the cell surface. In this issue of Science Signaling, Sundaram et al. demonstrate a protective role for iRhom2 in promoting ADAM17-mediated shedding of TNFRs in hepatic stellate cells, which reduces TNFR signaling and liver fibrosis in response to injury.
- Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerPublication . Currey, Nicola; Jahan, Zeenat; Caldon, C Elizabeth; Tran, Phuong N; Benthani, Fahad; De Lacavalerie, Penelope; Roden, Daniel L; Gloss, Brian S; Campos, Claudia; Bean, Elaine G; Bullman, Amanda; Reibe-Pal, Saskia; Dinger, Marcel E; Febbraio, Mark A; Clarke, Stephen J; Dahlstrom, Jane E; Kohonen-Corish, Maija R JThe early events by which inflammation promotes cancer are still not fully defined. The MCC gene is silenced by promoter methylation in colitis-associated and sporadic colon tumors, but its functional significance in precancerous lesions or polyps is not known. Here, we aimed to determine the impact of Mcc deletion on the cellular pathways and carcinogenesis associated with inflammation in the mouse proximal colon.
- A Comprehensive Review on the Interaction Between the Host GTPase Rab11 and Influenza A VirusPublication . Amorim, Maria JoãoThis year marks the 100th anniversary of one of the deadliest pandemic outbreaks, commonly referred as the Spanish Flu, that was caused by influenza A virus (IAV). Since then, IAV has been in governmental agendas worldwide, and a lot of effort has been put into understanding the pathogen's lifecycle, predict and mitigate the emergence of the strains that provoke yearly epidemics and pandemic events. Despite decades of research and seminal contributions there is still a lot to be investigated. In particular for this review, IAV lifecycle that takes place inside the host cell is not fully understood. Two steps that need clarification include genome transport to budding sites and genome assembly, the latter a complex process challenged by the nature of IAV genome that is divided into eight distinct parts. Assembly of such segmented genome is crucial to form fully infectious viral particles but is also critical for the emergence of viruses with pandemic potential that arise when avian and human IAV strains co-infect a host. The host GTPase Rab11 was separately implicated in both steps, and, interestingly these processes are beginning to emerge as being intimately related. Rab11 was initially proposed to be involved in the budding/release of IAV virions. It was subsequently shown to transport progeny genome, and later proposed to promote assembly of viral genome, but the underlying bridging mechanism the two is far from clear. For simplicity, this Rab11-centric review provides an initial separate account of Rab11 involvement in genome transport and in assembly. IAV genome assembly is a complicated molecular biology process, and therefore earned a dedicated section on how/if the viral genome forms a genomic supramolecular complex. Both topics present intricate challenges, outstanding questions, and unique controversies. At the end of the review, I will explore possible mechanisms intertwining IAV vRNP transport and genome assembly. Importantly, Rab11 has recently emerged as a key factor subverted by evolutionary unrelated viral families (Paramyxo, Bunya, and Orthomyxoviruses, among many others) and bacteria (Salmonella and Shigella) relevant to human health. This review provides a framework to identify common biological principles among the lifecycles of these pathogens.
- Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerPublication . Currey, Nicola; Jahan, Zeenat; Caldon, C. Elizabeth; Tran, Phuong N.; Benthani, Fahad; De Lacavalerie, Penelope; Roden, Daniel L.; Gloss, Brian S.; Campos, Claudia; Bean, Elaine G.; Bullman, Amanda; Reibe-Pal, Saskia; Dinger, Marcel E.; Febbraio, Mark A.; Clarke, Stephen J.; Dahlstrom, Jane E.; Kohonen-Corish, Maija R.J.The early events by which inflammation promotes cancer are still not fully defined. The MCC gene is silenced by promoter methylation in colitis-associated and sporadic colon tumors, but its functional significance in precancerous lesions or polyps is not known. Here, we aimed to determine the impact of Mcc deletion on the cellular pathways and carcinogenesis associated with inflammation in the mouse proximal colon.
- PLK4 is a microtubule-associated protein that self-assembles promoting de novo MTOC formationPublication . Montenegro Gouveia, Susana; Zitouni, Sihem; Kong, Dong; Duarte, Paulo; Ferreira Gomes, Beatriz; Sousa, Ana Laura; Tranfield, Erin M.; Hyman, Anthony; Loncarek, Jadranka; Bettencourt-Dias, MonicaThe centrosome is an important microtubule-organising centre (MTOC) in animal cells. It consists of two barrel-shaped structures, the centrioles, surrounded by the pericentriolar material (PCM), which nucleates microtubules. Centrosomes can form close to an existing structure (canonical duplication) or de novo How centrosomes form de novo is not known. The master driver of centrosome biogenesis, PLK4, is critical for the recruitment of several centriole components. Here, we investigate the beginning of centrosome biogenesis, taking advantage of Xenopus egg extracts, where PLK4 can induce de novo MTOC formation ( Eckerdt et al., 2011; Zitouni et al., 2016). Surprisingly, we observe that in vitro, PLK4 can self-assemble into condensates that recruit α- and β-tubulins. In Xenopus extracts, PLK4 assemblies additionally recruit STIL, a substrate of PLK4, and the microtubule nucleator γ-tubulin, forming acentriolar MTOCs de novo The assembly of these robust microtubule asters is independent of dynein, similar to what is found for centrosomes. We suggest a new mechanism of action for PLK4, where it forms a self-organising catalytic scaffold that recruits centriole components, PCM factors and α- and β-tubulins, leading to MTOC formation.This article has an associated First Person interview with the first author of the paper.
- Pericentrin-mediated SAS-6 recruitment promotes centriole assemblyPublication . Ito, Daisuke; Zitouni, Sihem; Jana, Swadhin Chandra; Duarte, Paulo; Surkont, Jaroslaw; Carvalho-Santos, Zita; Pereira-Leal, José B; Ferreira, Miguel Godinho; Bettencourt-Dias, MónicaThe centrosome is composed of two centrioles surrounded by a microtubule-nucleating pericentriolar material (PCM). Although centrioles are known to regulate PCM assembly, it is less known whether and how the PCM contributes to centriole assembly. Here we investigate the interaction between centriole components and the PCM by taking advantage of fission yeast, which has a centriole-free, PCM-containing centrosome, the SPB. Surprisingly, we observed that several ectopically-expressed animal centriole components such as SAS-6 are recruited to the SPB. We revealed that a conserved PCM component, Pcp1/pericentrin, interacts with and recruits SAS-6. This interaction is conserved and important for centriole assembly, particularly its elongation. We further explored how yeasts kept this interaction even after centriole loss and showed that the conserved calmodulin-binding region of Pcp1/pericentrin is critical for SAS-6 interaction. Our work suggests that the PCM not only recruits and concentrates microtubule-nucleators, but also the centriole assembly machinery, promoting biogenesis close by.
- Mutation S110L of H1N1 Influenza Virus Hemagglutinin: A Potent Determinant of Attenuation in the Mouse ModelPublication . Nieto, Amelia; Vasilijevic, Jasmina; Santos, Nuno Brito; Zamarreño, Noelia; López, Pablo; Amorim, Maria Joao; Falcon, AnaCharacterization of a pandemic 2009 H1N1 influenza virus isolated from a fatal case patient (F-IAV), showed the presence of three different mutations; potential determinants of its high pathogenicity that were located in the polymerase subunits (PB2 A221T and PA D529N) and the hemagglutinin (HA S110L). Recombinant viruses containing individually or in combination the polymerase mutations in the backbone of A/California/04/09 (CAL) showed that PA D529N was clearly involved in the increased pathogenicity of the F-IAV virus. Here, we have evaluated the contribution of HA S110L to F-IAV pathogenicity, through introduction of this point mutation in CAL recombinant virus (HA mut). The HA S110L protein has similar pH stability, comparable mobility, and entry properties both in human and mouse cultured cells that wild type HA. The change HA S110L leads to a non-significant trend to reduce the replication capacity of influenza virus in tissue culture, and HA mut is better neutralized than CAL virus by monoclonal and polyclonal antibodies against HA from CAL strain. In addition, recombinant viruses containing HA S110L alone or in combination with polymerase mutations considerably increased the LD50 in infected mice. Characterization of the lungs of HA mut infected animals showed reduced lung damage and inflammation compared with CAL infected mice. Accordingly, lower virus replication, decreased presence in bronchioli and parenchyma and lower leukocytes and epithelial infected cells were found in the lungs of HA mut-infected animals. Our results indicate that, mutation HA S110L constitutes a determinant of attenuation and suggest that its interaction with components of the respiratory tract mucus and lectins, that play an important role on influenza virus outcome, may constitute a physical barrier impeding the infection of the target cells, thus compromising the infection outcome.
- Two CRISPR/Cas9-mediated methods for targeting complex insertions, deletions, or replacements in mousePublication . Pineault, Kyriel M.; Novoa, Ana; Lozovska, Anastasiia; Wellik, Deneen M.; Mallo, MoisesGenetically modified model organisms are valuable tools for probing gene function, dissecting complex signaling networks, studying human disease, and more. CRISPR/Cas9 technology has significantly democratized and reduced the time and cost of generating genetically modified models to the point that small gene edits are now routinely and efficiently generated in as little as two months. However, generation of larger and more sophisticated gene-modifications continues to be inefficient. Alternative ways to provide the replacement DNA sequence, method of Cas9 delivery, and tethering the template sequence to Cas9 or the guide RNA (gRNA) have all been tested in an effort to maximize homology-directed repair for precise modification of the genome. We present two CRISPR/Cas9 methods that have been used to successfully generate large and complex gene-edits in mouse. In the first method, the Cas9 enzyme is used in conjunction with two sgRNAs and a long single-stranded DNA (lssDNA) template prepared by an alternative protocol. The second method utilizes a tethering approach to couple a biotinylated, double-stranded DNA (dsDNA) template to a Cas9-streptavidin fusion protein. •Alternative method for generating long, single-stranded DNA templates for CRISPR/Cas9 editing.•Demonstration that using two sgRNAs with Cas9-streptavidin/biotinylated-dsDNA is feasible for large DNA modifications.
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