Genome-wide synthetic lethal CRISPR screen identifies FIS1 as a genetic interactor of ALS-linked C9ORF72.

Mutations in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis (ALS). Both toxic gain of function and loss of function pathogenic mechanisms have been proposed. Accruing evidence from mouse knockout studies point to a role for C9ORF72 as a regulator of immune function. To provide further insight into its cellular function, we performed a genome-wide synthetic lethal CRISPR screen in human myeloid cells lacking C9ORF72. We discovered a strong synthetic lethal genetic interaction between C9ORF72 and FIS1, which encodes a mitochondrial membrane protein involved in mitochondrial fission and mitophagy. Mass spectrometry experiments revealed that in C9ORF72 knockout cells, FIS1 strongly bound to a class of immune regulators that activate the receptor for advanced glycation end (RAGE) products and trigger inflammatory cascades. These findings present a novel genetic interactor for C9ORF72 and suggest a compensatory role for FIS1 in suppressing inflammatory signaling in the absence of C9ORF72.

Role of freshwater floodplain-tidal slough complex in the persistence of the endangered delta smelt.

Seasonal floodplain wetland is one of the most variable and diverse habitats found in coastal ecosystems, yet it is also one of the most highly altered by humans. The Yolo Bypass, the primary floodplain of the Sacramento River in California's Central Valley, USA, has been shown to provide various benefits to native fishes when inundated. However, the Yolo Bypass exists as a tidal dead-end slough during dry periods and its value to native fishes has been less studied in this state. During the recent drought (2012-2016), we found higher abundance of the endangered Delta Smelt (Hypomesus transpacificus), than the previous 14 years of fish monitoring within the Yolo Bypass. Meanwhile, Delta Smelt abundance elsewhere in the estuary was at record lows during this time. To determine the value of the Yolo Bypass as a nursery habitat for Delta Smelt, we compared growth, hatch dates, and diets of juvenile Delta Smelt collected within the Yolo Bypass with fish collected among other putative nursery habitats in the San Francisco Estuary between 2010 and 2016. Our results indicated that when compared to other areas of the estuary, fish in the Yolo Bypass spawned earlier, and offspring experienced both higher quality feeding conditions and growth rates. The occurrence of healthy juvenile Delta Smelt in the Yolo Bypass suggested that the region may have acted as a refuge for the species during the drought years of 2012-2016. However, our results also demonstrated that no single region provided the best rearing habitat for juvenile Delta Smelt. It will likely require a mosaic of habitats that incorporates floodplain-tidal sloughs in order to promote the resilience of this declining estuarine fish species.

A Conservation Hatchery Population of Delta Smelt Shows Evidence of Genetic Adaptation to Captivity After 9 Generations.

Genetic adaptation to captivity is a concern for threatened and endangered species held in conservation hatcheries. Here, we present evidence of genetic adaptation to captivity in a conservation hatchery for the endangered delta smelt (Fish Conservation and Culture Laboratory, University of California Davis; FCCL). The FCCL population is genetically managed with parentage analysis and the addition of wild fish each year. Molecular monitoring indicates little loss of genetic variation and low differentiation between the wild and conservation populations. Yet, we found an increase in offspring survival to reproductive maturity during the subsequent spawning season (recovery rate) in crosses that included one or both cultured parents. Crosses with higher levels of hatchery ancestry tend to produce a greater number of offspring that are recovered the following year. The recovery rate of a cross decreases when offspring are raised in a tank with fish of high levels of hatchery ancestry. We suggest changes in fish rearing practices at the FCCL to reduce genetic adaptation to captivity, as delta smelt numbers in the wild continue to decline and the use of FCCL fish for reintroduction becomes more likely.

Myocardial wall stiffening in a mouse model of persistent truncus arteriosus.

BACKGROUND: Genetic and epigenetic programs regulate dramatic structural changes during cardiac morphogenesis. Concurrent biomechanical forces within the heart created by blood flow and pressure in turn drive downstream cellular, molecular and genetic responses. Thus, a genetic-morphogenetic-biomechanical feedback loop is continually operating to regulate heart development. During the evolution of a congenital heart defect, concomitant abnormalities in blood flow, hemodynamics, and patterns of mechanical loading would be predicted to change the output of this feedback loop, impacting not only the ultimate morphology of the defect, but potentially altering tissue-level biomechanical properties of structures that appear structurally normal. AIM: The goal of this study was to determine if abnormal hemodynamics present during outflow tract formation and remodeling in a genetically engineered mouse model of persistent truncus arteriosus (PTA) causes tissue-level biomechanical abnormalities. METHODS: The passive stiffness of surface locations on the left ventricle (LV), right ventricle (RV), and outflow tract (OFT) was measured with a pipette aspiration technique in Fgf8;Isl1Cre conditional mutant embryonic mouse hearts and controls. Control and mutant experimental results were compared by a strain energy metric based on the measured relationship between pressure and aspirated height, and also used as target behavior for finite element models of the ventricles. Model geometry was determined from 3D reconstructions of whole-mount, confocal-imaged hearts. The stress-strain relationship of the model was adjusted to achieve an optimal match between model and experimental behavior. RESULTS AND CONCLUSION: Although the OFT is the most severely affected structure in Fgf8;Isl1Cre hearts, its passive stiffness was the same as in control hearts. In contrast, both the LV and RV showed markedly increased passive stiffness, doubling in LVs and quadrupling in RVs of mutant hearts. These differences are not attributable to differences in ventricular volume, wall thickness, or trabecular density. Excellent agreement was obtained between the model and experimental results. Overall our findings show that hearts developing PTA have early changes in ventricular tissue biomechanics relevant to cardiac function and ongoing development.