Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats.

Expansion of a hexanucleotide repeat in a noncoding region of the C9ORF72 gene is responsible for a significant fraction of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) cases, but identifying specific toxic gene products and mechanisms has been difficult. Pathogenesis was proposed to involve the production of toxic RNA species and/or accumulation of toxic dipeptide repeats (DPRs), but distinguishing between these mechanisms has been challenging. In this study, we first use complementary model systems for analyzing pathogenesis in adult-onset neurodegenerative diseases to characterize the pathogenicity of DPRs produced by Repeat Associated Non-ATG (RAN) translation of C9ORF72 in specific cellular compartments: isolated axoplasm and giant synapse from the squid. Results showed selective axonal and presynaptic toxicity of GP-DPRs, independent of associated RNA. These effects involved downstream ASK1 signaling pathways that affect fast axonal transport and synaptic function, a pathogenic mechanism shared with other mutant proteins associated with familial ALS, like SOD1 and FUS. These pathways are sufficient to produce the "dying-back" axonopathy seen in ALS. However, other mutant genes (e.g., SOD1) that activate this mechanism rarely produce FTD. When parallel studies in primary motor neurons from rats were conducted, an additional pathogenic mechanism was revealed. The GR- and PR-DPRs, which had no effect on axonal transport or synaptic transmission, were found to disrupt the nuclei of transfected neurons, leading to "dying-forward" neuropathy. All C9-DRP-mediated toxic effects observed here are independent of whether the corresponding mRNAs contained hexanucleotide repeats or alternative codons. These studies establish the divergent toxicity of C9-DPRs that cause neurodegeneration in ALS and FTD, suggesting that these two independent pathogenic mechanisms may contribute to disease heterogeneity and/or synergize on disease progression in C9ORF72 patients with both ALS and FTD symptoms.

Building consensus around the assessment and interpretation of Symbiodiniaceae diversity.

Within microeukaryotes, genetic variation and functional variation sometimes accumulate more quickly than morphological differences. To understand the evolutionary history and ecology of such lineages, it is key to examine diversity at multiple levels of organization. In the dinoflagellate family Symbiodiniaceae, which can form endosymbioses with cnidarians (e.g., corals, octocorals, sea anemones, jellyfish), other marine invertebrates (e.g., sponges, molluscs, flatworms), and protists (e.g., foraminifera), molecular data have been used extensively over the past three decades to describe phenotypes and to make evolutionary and ecological inferences. Despite advances in Symbiodiniaceae genomics, a lack of consensus among researchers with respect to interpreting genetic data has slowed progress in the field and acted as a barrier to reconciling observations. Here, we identify key challenges regarding the assessment and interpretation of Symbiodiniaceae genetic diversity across three levels: species, populations, and communities. We summarize areas of agreement and highlight techniques and approaches that are broadly accepted. In areas where debate remains, we identify unresolved issues and discuss technologies and approaches that can help to fill knowledge gaps related to genetic and phenotypic diversity. We also discuss ways to stimulate progress, in particular by fostering a more inclusive and collaborative research community. We hope that this perspective will inspire and accelerate coral reef science by serving as a resource to those designing experiments, publishing research, and applying for funding related to Symbiodiniaceae and their symbiotic partnerships.

Distinct Phenotypes Associated with Mangrove and Lagoon Habitats in Two Widespread Caribbean Corals, Porites astreoides and Porites divaricata.

AbstractAs coral reefs experience dramatic declines in coral cover throughout the tropics, there is an urgent need to understand the role that non-reef habitats, such as mangroves, play in the ecological niche of corals. Mangrove habitats present a challenge to reef-dwelling corals because they can differ dramatically from adjacent reef habitats with respect to key environmental parameters, such as light. Because variation in light within reef habitats is known to drive intraspecific differences in coral phenotype, we hypothesized that coral species that can exploit both reef and mangrove habitats will exhibit predictable differences in phenotypes between habitats. To investigate how intraspecific variation, driven by either local adaptation or phenotypic plasticity, might enable particular coral species to exploit these two qualitatively different habitat types, we compared the phenotypes of two widespread Caribbean corals, Porites divaricata and Porites astreoides, in mangrove versus lagoon habitats on Turneffe Atoll, Belize. We document significant differences in colony size, color, structural complexity, and corallite morphology between habitats. In every instance, the phenotypic differences between mangrove prop root and lagoon corals exhibited consistent trends in both P. divaricata and P. astreoides. We believe this study is the first to document intraspecific phenotypic diversity in corals occupying mangrove prop root versus lagoonal patch reef habitats. A difference in the capacity to adopt an alternative phenotype that is well suited to the mangrove habitat may explain why some reef coral species can exploit mangroves, while others cannot.

A framework for understanding gene expression plasticity and its influence on stress tolerance.

Phenotypic plasticity can serve as a stepping stone towards adaptation. Recently, studies have shown that gene expression contributes to emergent stress responses such as thermal tolerance, with tolerant and susceptible populations showing distinct transcriptional profiles. However, given the dynamic nature of gene expression, interpreting transcriptomic results in a way that elucidates the functional connection between gene expression and the observed stress response is challenging. Here, we present a conceptual framework to guide interpretation of gene expression reaction norms in the context of stress tolerance. We consider the evolutionary and adaptive potential of gene expression reaction norms and discuss the influence of sampling timing, transcriptomic resilience, as well as complexities related to life history when interpreting gene expression dynamics and how these patterns relate to host tolerance. We highlight corals as a case study to demonstrate the value of this framework for non-model systems. As species face rapidly changing environmental conditions, modulating gene expression can serve as a mechanistic link from genetic and cellular processes to the physiological responses that allow organisms to thrive under novel conditions. Interpreting how or whether a species can employ gene expression plasticity to ensure short-term survival will be critical for understanding the global impacts of climate change across diverse taxa.