Neuroinflammation is a hallmark of Alzheimer's disease (AD) both in man and in multiple mouse models, and epidemiological studies link the use of anti-inflammatory drugs with a reduced risk of developing the disease. AD-related neuroinflammation is largely mediated by microglia, the main immune cells of the central nervous system. In vitro, executive functions of microglia are regulated by intracellular Ca(2+) signals, but little is known about microglial Ca(2+) signaling in vivo. Here we analyze in vivo properties of these cells in two mouse models of AD. In both strains plaque-associated microglia had hypertrophic/amoeboid morphology and were strongly positive for markers of activation such as CD11b and CD68. Activated microglia failed to respond reliably to extracellular release of adenosine triphosphate (ATP, mimicking tissue damage) and showed an increased incidence of spontaneous intracellular Ca(2+) transients. These Ca(2+) transients required activation of ATP receptors and Ca(2+) release from the intracellular Ca(2+) stores, and were not induced by neuronal or astrocytic hyperactivity. Neuronal silencing, however, selectively increased the frequency of Ca(2+) transients in plaque-associated microglia. Thus, our in vivo data reveal substantial dysfunction of plaque-associated microglia and identify a novel Ca(2+) signal possibly triggering a Ca(2+)-dependent release of toxic species in the plaque vicinity.

Keywords: Alzheimer's disease r In vivo imaging r Microglia r Tomato lectin

The Drosophila heart is a linear organ formed by the movement of bilaterally specified progenitor cells to the midline and adherence of contralateral heart cells. This movement occurs through the attachment of heart cells to the overlying ectoderm which is undergoing dorsal closure. Therefore heart cells are thought to move to the midline passively. Through live imaging experiments and analysis of mutants that affect the speed of dorsal closure we show that heart cells in Drosophila are autonomously migratory and part of their movement to the midline is independent of the ectoderm. This means that heart formation in flies is more similar to that in vertebrates than previously thought. We also show that defects in dorsal closure can result in failure of the amnioserosa to properly degenerate, which can physically hinder joining of contralateral heart cells leading to a broken heart phenotype.

Neonatal hypoxia-ischemia encephalopathy (HIE) refers to a brain injury in term infants that can lead to death or lifelong neurological deficits such as cerebral palsy (CP). The pathogenesis of this disease involves multiple cellular and molecular events, notably a neuroinflammatory response driven partly by microglia, the brain resident macrophages. Treatment options are currently very limited, but stem cell (SC) therapy holds promise, as beneficial outcomes are reported in animal studies and to a lesser degree in human trials. Among putative mechanisms of action, immunomodulation is considered a major contributor to SC associated benefits. The goal of this review is to examine whether microglia is a cellular target of SC-mediated immunomodulation and whether the recruitment of microglia is linked to brain repair. We will first provide an overview on microglial activation in the rodent model of neonatal HI, and highlight its sensitivity to developmental age. Two complementary questions are then addressed: (i) do immune-related treatments impact microglia and provide neuroprotection, (ii) does stem cell treatment modulates microglia? Finally, the immune-related findings in patients enrolled in SC based clinical trials are discussed. Our review points to an impact of SCs on the microglial phenotype, but heterogeneity in experimental designs and methodological limitations hamper our understanding of a potential contribution of microglia to SC associated benefits. Thorough analyses of the microglial phenotype are warranted to better address the relevance of the neuroimmune crosstalk in brain repair and improve or advance the development of SC protocols in humans. Graphical abstract

During development, the pancreatic endocrine cells are specified within the epithelium. They will subsequently delaminate and migrate out of the epithelium in order to form the islets.Neurogenin3 (Ngn3) is a bHLH transcription factor that is responsible for differentiation of all endocrine cell types, but whether or not it has a role in their migration is still an open question. By using the chicken embryo model organism, we found that differentiation and migration programs are two different processes that are induced by Ngn3 and that can be uncoupled. Therefore, we tried to unravel the mechanisms by which Ngn3 can induce endocrine cell migration. We found that, both in chick and mouse models, overexpression of Ngn3 induces a loss of apico-basal polarity, a breakdown of basal lamina, and more importantly, a loss of the epithelial marker E-cadherin (Ecad). We also found that this is not a direct effect mediated by E-boxes in the Ecad promoter. Therefore, we are currently trying to find targets of Ngn3 that could mediate repression of Ecad, focalizing on the zinc-finger transcription factors Snail and Slug. Moreover, we are also using a pancreatic explant culture method, developed in the laboratory of Pr. Jonathan Slack, that allows us to do time-lapse imaging. Taking advantage of our Pdx::Ngn3 ERTM transgenic line, we are following Ngn3 overexpressing cells to understand in a more physiological manner how they migrate in the developing pancreas.Recent studies have provided evidence that bHLH transcription factors such as Neurogenin (Ngn) and Mash1 regulate neuronal migration (Hand et al., 2005; Ge et al., 2006). Rnd2 has been found to mediate Ngn2 activity in cell migration in the cerebral cortex (Heng et al., 2008). However, the mechanisms by which Mash1 regulates neuronal migration appear to be different and are still unknown.By screening putative Mash1 targets identified in expression microarray experiments, we found genes that regulate cell migration in other systems like RhoE/Rnd3. As its role in the developing nervous system has not yet been addressed, we have begun to study the role of Rnd3 in the radial migration of cortical neurons. Rnd3 knock-down in the dorsal telencephalon at E14.5 results in radial migration defects of cortical neurons and increases the fraction of dividing progenitors. These migration defects are due to a distinct function of Rnd3 in post-mitotic neurons. Moreover Rnd3 silencing affects the morphology of migrating neurons. Mash1 is required for Rnd3 expression in the telencephalon and conserved Mash1 binding sites (E-boxes) are located in noncoding sequences of Rnd3 gene. Some of these E-boxes are able to bind Mash1 suggesting that this proneural factor directly regulates Rnd3 expression in telencephalic neurons. These results demonstrate that the Mash1-Rnd3 pathway plays a critical role in the migration of projection neurons in the developing telencephalon. The expression, regulation and knockdown phenotypes of Rnd2 and Rnd3 also indicate that the two genes are part of different reg...