Regulation of N-cadherin-based cell–cell interaction by JSAP1

金沢大学がん研究所がん分子細胞制御金沢大学大学院医学系研究科We previously reported that the level of c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1), a scaffold protein for JNK signaling, increases dramatically during nerve growth factor (NGF)-induced differentiation of PC12h cells. In the present study, we investigated the function of JSAP1 during PC12h cell differentiation by knocking down the level of JSAP1. The depletion of JSAP1 caused NGF-treated PC12h cells to form aggregates and impaired their differentiation. The aggregation was not observed in JSAP1-depleted cells that were untreated or treated with epidermal growth factor. Immunocytochemical studies indicated that N-cadherin, but not E-cadherin, was localized to sites of cell–cell contact in the aggregated cells. Furthermore, an inhibitory anti-N-cadherin antibody completely blocked the aggregation. Taken together, these results suggest that JSAP1 regulates cell–cell interactions in PC12h cells specifically in the NGF-induced signaling pathway, and does so by modulating N-cadherin

GPR measurements to assess the Emeelt active fault's characteristics in a highly smooth topographic context, Mongolia

International audienceTo estimate the seismic hazard, the geometry (dip, length and orientation) and the dynamics (type of displacements and amplitude) of the faults in the area of interest need to be understood. In this paper, in addition to geomorphologic observations, we present the results of two ground penetrating radar (GPR) campaigns conducted in 2010 and 2011 along the Emeelt fault in the vicinity of Ulaanbaatar, capital of Mongolia, located in an intracontinental region with low deformation rate that induces long recurrence time between large earthquakes. As the geomorphology induced by the fault activity has been highly smoothed by erosion processes since the last event, the fault location and geometry is difficult to determine precisely. However, by using GPR first, a non-destructive and fast investigation, the fault and the sedimentary deposits near the surface can be characterized and the results can be used for the choice of trench location. GPR was performed with a 50 MHz antenna over 2-D lines and with a 500 MHz antenna for pseudo-3-D surveys. The 500 MHz GPR profiles show a good consistency with the trench observations, dug next to the pseudo-3-D surveys. The 3-D 500 MHz GPR imaging of a palaeochannel crossed by the fault allowed us to estimate its lateral displacement to be about 2 m. This is consistent with a right lateral strike-slip displacement induced by an earthquake around magnitude 7 or several around magnitude 6. The 2-D 50 MHz profiles, recorded perpendicular to the fault, show a strong reflection dipping to the NE, which corresponds to the fault plane. Those profiles provided complementary information on the fault such as its location at shallow depth, its dip angle (from 23 • to 35 •) and define its lateral extension. Central Asia is known for its high level of seismic hazards, especially Mongolia, which has been one of the most seismically active intracontinental regions in the world with four large earthquakes (magnitude around 8) along its active faults in the western part of the country during the last century (Khilko et al. 1985). The deformation in Mongolia is located between compressive structures related to the collision and penetration of the Indian plate into the Eurasian plate and extensive structures in the north of the country related with the Baykal rift (Tapponnier & Molnar 1979; Baljinnyam et al. 1993; Schlupp 1996; Bayasgalan & Jackson 1999). The seismic activity observed in the vicinity of Ulaanbaatar (UB), capital of Mongolia, is relatively low compared to the activity observed in western Mongolia. Nevertheless, since 2005, the seismic activity around UB not only has increased, but is also organized (see Fig. 1) at the west of UB along two perpendicular directions, which determine two active faults: Emeelt fault, discovered in 2008 (NNW-SSE direction, 25-km-long minimum and situated about 10 km W of UB) and Hustai fault (WSW–ENE direction, 80 km long, with its NE tip at less than 20 km west of UB); their length and morphology indicate that they can produce earthquakes of magnitude 6.5–7.5 (Schlupp et al. 2012). Most of the Mongolian population (1.2 million over 3 million) is concentrated at UB, which is the main political and economical centre of the country. Hence, the study of seismic hazard and the estimation of the probability of future destructive earthquakes are of primary importance for the country (Dugarmaa et al. 2006). Since the last large earthquake, the faults geomorphology has been highly smoothed by erosional processes and the exact location of the fault plane surface rupture is thus hidden within a several metre wide strip. The GPR method has been proven to give good and useful results to characterize faults by identifying offsets of radar reflections (Malik et al. 2007; Christie et al. 2009; Yalçiner et al. 2013) an

25,000 Years long seismic cycle in a slow deforming continental region of Mongolia

International audienc

Dominant Mutations in KBTBD13, a Member of the BTB/Kelch Family, Cause Nemaline Myopathy with Cores

We identified a member of the BTB/Kelch protein family that is mutated in nemaline myopathy type 6 (NEM6), an autosomal-dominant neuromuscular disorder characterized by the presence of nemaline rods and core lesions in the skeletal myofibers. Analysis of affected families allowed narrowing of the candidate region on chromosome 15q22.31, and mutation screening led to the identification of a previously uncharacterized gene, KBTBD13, coding for a hypothetical protein and containing missense mutations that perfectly cosegregate with nemaline myopathy in the studied families. KBTBD13 contains a BTB/POZ domain and five Kelch repeats and is expressed primarily in skeletal and cardiac muscle. The identified disease-associated mutations, C.742C>A (p.Arg248Ser), c.1170G>C (p.Lys390Asn), and c.1222C>T (p.Arg408Cys), located in conserved domains of Kelch repeats, are predicted to disrupt the molecule's beta-propeller blades. Previously identified BTB/POZ/Kelch-domain-containing proteins have been implicated in a broad variety of biological processes, including cytoskeleton modulation, regulation of gene transcription, ubiquitination, and myofibril assembly. The functional role of KBTBD13 in skeletal muscle and the pathogenesis of NEM6 are subjects for further studies

In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy

Myofibrillar myopathies (MFMs) are an expanding and increasingly recognized group of neuromuscular disorders caused by mutations in DES, CRYAB, MYOT, and ZASP. The latest gene to be associated with MFM was FLNC; a p.W2710X mutation in the 24th immunoglobulin-like repeat of filamin C was shown to be the cause of a distinct type of MFM in several German families. We studied an International cohort of 46 patients from 39 families with clinically and myopathologically confirmed MFM, in which DES, CRYAB, MYOT, and ZASP mutations have been excluded. In patients from an unrelated family a 12-nucleotide deletion (c.2997_3008del) in FLNC resulting in a predicted in-frame four-residue deletion (p.Val930_Thr933del) in the seventh repeat of filamin C was identified. Both affected family members, mother and daughter, but not unrelated control individuals, carried the p.Val930_Thr933del mutation. The mutation is transcribed and, based on myopathological features and immunoblot analysis, it leads to an accumulation of dysfunctional filamin C in the myocytes. The study results suggest that the novel p.Val930_Thr933del mutation in filamin C is the cause of MFM but also indicate that filamin C mutations are a comparatively rare cause of MFM