Murine Dishevelled 3 Functions in Redundant Pathways with Dishevelled 1 and 2 in Normal Cardiac Outflow Tract, Cochlea, and Neural Tube Development

Dishevelled (Dvl) proteins are important signaling components of both the canonical β-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3−/− mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+). Although neurulation appeared normal in both Dvl3−/− and LtapLp/+ mutants, Dvl3+/−;LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant

Murine Dishevelled 3 Functions in Redundant Pathways with Dishevelled 1 and 2 in Normal Cardiac Outflow Tract, Cochlea, and Neural Tube Development

Dishevelled (Dvl) proteins are important signaling components of both the canonical β-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3−/− mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+). Although neurulation appeared normal in both Dvl3−/− and LtapLp/+ mutants, Dvl3+/−;LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant

Intracranial V. cholerae Sialidase Protects against Excitotoxic Neurodegeneration

Converging evidence shows that GD3 ganglioside is a critical effector in a number of apoptotic pathways, and GM1 ganglioside has neuroprotective and noötropic properties. Targeted deletion of GD3 synthase (GD3S) eliminates GD3 and increases GM1 levels. Primary neurons from GD3S−/− mice are resistant to neurotoxicity induced by amyloid-β or hyperhomocysteinemia, and when GD3S is eliminated in the APP/PSEN1 double-transgenic model of Alzheimer's disease the plaque-associated oxidative stress and inflammatory response are absent. To date, no small-molecule inhibitor of GD3S exists. In the present study we used sialidase from Vibrio cholerae (VCS) to produce a brain ganglioside profile that approximates that of GD3S deletion. VCS hydrolyzes GD1a and complex b-series gangliosides to GM1, and the apoptogenic GD3 is degraded. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. Sensorimotor behaviors, anxiety, and cognition were unaffected in VCS-treated mice. To determine whether VCS was neuroprotective in vivo, we injected kainic acid on the 25th day of infusion to induce status epilepticus. Kainic acid induced a robust lesion of the CA3 hippocampal subfield in aCSF-treated controls. In contrast, all hippocampal regions in VCS-treated mice were largely intact. VCS did not protect against seizures. These results demonstrate that strategic degradation of complex gangliosides and GD3 can be used to achieve neuroprotection without adversely affecting behavior

Synaptic Wnt signaling—a contributor to major psychiatric disorders?

Wnt signaling is a key pathway that helps organize development of the nervous system. It influences cell proliferation, cell fate, and cell migration in the developing nervous system, as well as axon guidance, dendrite development, and synapse formation. Given this wide range of roles, dysregulation of Wnt signaling could have any number of deleterious effects on neural development and thereby contribute in many different ways to the pathogenesis of neurodevelopmental disorders. Some major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders, are coming to be understood as subtle dysregulations of nervous system development, particularly of synapse formation and maintenance. This review will therefore touch on the importance of Wnt signaling to neurodevelopment generally, while focusing on accumulating evidence for a synaptic role of Wnt signaling. These observations will be discussed in the context of current understanding of the neurodevelopmental bases of major psychiatric diseases, spotlighting schizophrenia, bipolar disorder, and autism spectrum disorder. In short, this review will focus on the potential role of synapse formation and maintenance in major psychiatric disorders and summarize evidence that defective Wnt signaling could contribute to their pathogenesis via effects on these late neural differentiation processes

Earthquake Sources, the Stress Field and Seismic Hazard : A Study in Eritrea and its Surrounding

Presented in this thesis are some basic concepts and applications of seismic hazard analysis and the elements that influence the amplitude and geometric attenuation of earthquake ground motion. This thesis centers on the identification of the styles of failure, focal mechanisms, and the state of regional stress in the study area. Seismic hazard is a complex problem often involving considerable uncertainties. Therefore it is reasonable to consider different seismic hazard analysis approaches in order to as robustly as possible define zones of different levels of hazard. With the aim of characterizing and quantifying hazard in the east African region of Eritrea and its surroundings, a study is included in the thesis presenting hazard maps constructed using two non-parametric probabilistic seismic hazard analysis (PSHA) approaches. Peak ground acceleration (PGA) values for 10% probability of exceedence in 50 years are computed at given grid points for the whole selected area and results from both methods are compared. Other aspects addressed in the thesis include the determination of source parameters of selected earthquakes that occur in the Afar region. The styles of faulting, the mechanisms involved during the rupture process and the states of stress along the major tectonic features are also highlighted. Source parameters for selected events in the region were re-evaluated and improved solutions obtained. An aftershock sequence in the Hengill volcanic area in SW Iceland, following the major event that occurred on June 4, 1998, was used to investigate improved methodologies for moment tensor using a relative approach. The sensitive and spatially dense seismic network in this area reveals large sets of clustered events allowing the power of the new methodology to be demonstrated and providing greater insight into the tectonic implications of the activity in the area

Earthquake Sources, the Stress Field and Seismic Hazard : A Study in Eritrea and its Surrounding

Presented in this thesis are some basic concepts and applications of seismic hazard analysis and the elements that influence the amplitude and geometric attenuation of earthquake ground motion. This thesis centers on the identification of the styles of failure, focal mechanisms, and the state of regional stress in the study area. Seismic hazard is a complex problem often involving considerable uncertainties. Therefore it is reasonable to consider different seismic hazard analysis approaches in order to as robustly as possible define zones of different levels of hazard. With the aim of characterizing and quantifying hazard in the east African region of Eritrea and its surroundings, a study is included in the thesis presenting hazard maps constructed using two non-parametric probabilistic seismic hazard analysis (PSHA) approaches. Peak ground acceleration (PGA) values for 10% probability of exceedence in 50 years are computed at given grid points for the whole selected area and results from both methods are compared. Other aspects addressed in the thesis include the determination of source parameters of selected earthquakes that occur in the Afar region. The styles of faulting, the mechanisms involved during the rupture process and the states of stress along the major tectonic features are also highlighted. Source parameters for selected events in the region were re-evaluated and improved solutions obtained. An aftershock sequence in the Hengill volcanic area in SW Iceland, following the major event that occurred on June 4, 1998, was used to investigate improved methodologies for moment tensor using a relative approach. The sensitive and spatially dense seismic network in this area reveals large sets of clustered events allowing the power of the new methodology to be demonstrated and providing greater insight into the tectonic implications of the activity in the area