Toll-like receptors modulate adult hippocampal neurogenesis

Neurogenesis - the formation of new neurons in the adult brain - is considered to be one of the mechanisms by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes. The mechanisms underlying the regulation of neurogenesis are largely unknown. Here, we show that Toll-like receptors (TLRs), a family of highly conserved pattern-recognizing receptors involved in neural system development in Drosophila and innate immune activity in mammals, regulate adult hippocampal neurogenesis. We show that TLR2 and TLR4 are found on adult neural stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both in vitro and in vivo. TLR2 deficiency in mice impaired hippocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentiation. In vitro studies further indicated that TLR2 and TLR4 directly modulated self-renewal and the cell-fate decision of NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKCalpha/beta-dependent activation of the NF-kappaB signalling pathway. Thus, our study identified TLRs as players in adult neurogenesis and emphasizes their specified and diverse role in cell renewal.     

Novel terpenoids of the fungus Aspergillus insuetus isolated from the Mediterranean sponge Psammocinia sp. collected along the coast of Israel

Three novel meroterpenoids, insuetolides A-C (1-3) and four drimane sesquiterpenes, the new (E)-6-(4'-hydroxy-2'-butenoyl)-strobilactone A (4) and the known 2α, 9α, 11-trihydroxy-6-oxodrim-7-ene (5), strobilactone A (6) and (E,E)-6-(6',7'-dihydroxy-2',4'-octadienoyl)-strobilactone A (7), were isolated from the EtOAc extract of the culture medium of the marine-derived fungus Aspergillus insuetus (OY-207), which was isolated from the Mediterranean sponge Psammocinia sp. The structures of the compounds were determined by spectroscopic methods. Insuetolides A-C reveal a new carbon skeleton derived from the cyclization of farnesyl and 3, 5-dimethylorsellinic acid. Compounds 1, 6, and 7 exhibited anti-fungal activity towards Neurospora crassa with MIC values of 140, 242, and 162 μM, respectively; and compounds 3, 4, and 7 exhibited mild cytotoxicity towards MOLT-4 human leukemia cells.     

Diffusion MRI of structural brain plasticity induced by a learning and memory task

Background

Activity-induced structural remodeling of dendritic spines and glial cells was recently proposed as an important factor in neuroplasticity and suggested to accompany the induction of long-term potentiation (LTP). Although T1 and diffusion MRI have been used to study structural changes resulting from long-term training, the cellular basis of the findings obtained and their relationship to neuroplasticity are poorly understood.

Methodology/Principal Finding

Here we used diffusion tensor imaging (DTI) to examine the microstructural manifestations of neuroplasticity in rats that performed a spatial navigation task. We found that DTI can be used to define the selective localization of neuroplasticity induced by different tasks and that this process is age-dependent in cingulate cortex and corpus callosum and age-independent in the dentate gyrus.

Conclusion/Significance

We relate the observed DTI changes to the structural plasticity that occurs in astrocytes and discuss the potential of MRI for probing structural neuroplasticity and hence indirectly localizing LTP.     

The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway

Members of the low density lipoprotein receptor family (LDLR), LRP5/6, were shown to interact with the Frizzled (Fz) receptors and to function as Wnt coreceptors. Here we show that mLRP4T100, a minireceptor of LRP1, another member of the LDLR family, interacts with the human Fz-1 (HFz1), previously shown to serve as a receptor transmitting the canonical Wnt-3a-induced signaling cascade. However, in contrast to LRP5/6, mLRP4T100, as well as the full-length LRP1, did not cooperate with HFz1 in transmitting the Wnt-3a signaling but rather repressed it. mLRP4T100 inhibitory effect was displayed also by endocytosis-defective mLRP4T100 mutants, suggesting that LRP1 repressive effect is not attributable to LRP1-mediated enhanced HFz1 internalization and subsequent degradation. Enforced expression of mLRP4T100 decreased the capacity of HFz1 cysteine-rich domain (CRD) to interact with LRP6, in contrast to HFz1-CRD/Wnt-3a interaction that was not disrupted by overexpressing mLRP4T100. These data suggest that LRP1, by sequestering HFz1, disrupts the receptor/coreceptor complex formation, leading to the repression of the canonical Wnt signaling. Thus, this study implies that the ability to interact with Fz receptors is shared by several members of the LDLR family. However, whereas some members of the LDLR family, such as LRP5/6, interact with Fz and serve as Wnt coreceptors, others negatively regulate Wnt signaling, presumably by sequestering Fz.     

Our perception of developmental plasticity: esse est percipi (to be is to be perceived)?

The continuing interest in the biology of stem cells is enhanced by new discoveries surrounding developmental plasticity of both embryonic and adult stem cells. Adoptive transfer of concepts and definitions from the hematopoietic system to other tissue stem cells suggests inclusion of characteristics such as ability to self-renew and differentiate to functionally reconstitute a tissue/organ of origin. How adequate and accurate are these definitions? Within the great unknown of how these cells function, modulate their gene expression patterns and respond to extrinsic signals, it is apparent that there are numerous levels of stemness. We may envision a scale of developmental flexibility. At one end of the scale are positioned the embryonic stem cells, and at the other end are positioned partially-differentiated, differentiation restricted (committed) tissue/organ stem cells. There is evidence that some stem cells in the adult are pluripotent, thus positioned close to the embryonic end of the stem scale. It is uncertain yet to what extent stem cells can move back and forth along the stem scale.     

The NRAMP family of metal-ion transporters

The family of NRAMP metal ion transporters functions in diverse organisms from bacteria to human. NRAMP1 functions in metal transport across the phagosomal membrane of macrophages, and defective NRAMP1 causes sensitivity to several intracellular pathogens. DCT1 (NRAMP2) transport metal ions at the plasma membrane of cells of both the duodenum and in peripheral tissues, and defective DCT1 cause anemia. The driving force for the metal-ion transport is proton gradient (protonmotive force). In DCT1 the stoichiometry between metal ion and proton varied at different conditions due to a mechanistic proton slip. Though the metal ion transport by Smf1p, the yeast homolog of DCT1, is also a protonmotive force, a slippage of sodium ions was observed. The mechanism of the above phenomena could be explained by a combination between transporter and channel mechanisms.     

Live imaging of lymphatic development in the zebrafish

The lymphatic system has become the subject of great interest in recent years because of its important role in normal and pathological processes. Progress in understanding the origins and early development of this system, however, has been hampered by difficulties in observing lymphatic cells in vivo and in performing defined genetic and experimental manipulation of the lymphatic system in currently available model organisms. Here, we show that the optically clear developing zebrafish provides a useful model for imaging and studying lymphatic development, with a lymphatic system that shares many of the morphological, molecular and functional characteristics of the lymphatic vessels found in other vertebrates. Using two-photon time-lapse imaging of transgenic zebrafish, we trace the migration and lineage of individual cells incorporating into the lymphatic endothelium. Our results show lymphatic endothelial cells of the thoracic duct arise from primitive veins through a novel and unexpected pathway.     

Inbreeding and haploid chromosomes: a response to Hedrick (2011)

We have shown that inbreeding allows maternally transmitted organelles to respond to selection on male-specific fitness effects (Wade and Brandvain 2009, see also Unckless and Herren 2009). Hedrick (2011) confirms our results, but takes issue with our characterization of "inbreeding" at mitochondrial loci. The reason for this disagreement is straightforward-we define inbreeding as the process of mating between relatives, whereas Hedrick (2011) defines inbreeding as increased homozygosity at autosomal loci genome-wide, which occurs because of mating between relatives. Here, we insist that our definition is not incorrect, and highlight some benefits of our view.