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Caspases are at the core of executing apoptosis by orchestrating cellular destruction with proteolytic cascades. Caspase-mediated proteolysis also controls diverse nonlethal cellular activities such as proliferation, differentiation, cell fate decision, and cytoskeletal reorganization. During the last decade or so, genetic studies of Drosophila have contributed to our understanding of the in vivo mechanism of the non-apoptotic cellular responses in developmental contexts. Furthermore, recent studies using C. elegans suggest that apoptotic signaling may play unexpected roles, which influence ageing and normal development at the organism level. In this review, we describe how the caspase activity is elaborately controlled during vital cellular processes at the level of subcellular localization, the duration and timing to avoid full apoptotic consequences, and also discuss the novel roles of non-apoptotic caspase signaling in adult homeostasis and physiology.

The gustatory system plays an important role in evaluating food quality in animals and humans. While some tastes are intrinsically appetitive, such as sweet, which is elicited from high‐calorie nutrients, the other tastes, such as sour and bitter, are aversive and elicited by toxic substances. In mice, taste signals are relayed by multiple regions of the brain, including the nucleus of the solitary tract, and the parabrachial nucleus (PBN) of the pons, before reaching the gustatory cortex via the gustatory thalamus. Recent advances in taste research using mice expressing Cre recombinase in specific neuronal populations, together with chemogenetic/optogenetic tools, have enabled us to identify genetically defined neurons involved in taste transduction pathways across several areas of the brain. While gustatory pathways play a fundamental role in taste transduction, taste preferences are not always stable, but rather vary depending on internal states. This review summarizes recent progress in research on neural circuits that modify the taste information depending on internal states in mice.

The gustatory system plays a critical role in sensing appetitive and aversive taste stimuli for evaluating food quality. Although taste preference is known to change depending on internal states such as hunger, a mechanistic insight remains unclear. Here, we examine the neuronal mechanisms regulating hunger-induced taste modification. Starved mice exhibit an increased preference for sweetness and tolerance for aversive taste. This hunger-induced taste modification is recapitulated by selective activation of orexigenic Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus projecting to the lateral hypothalamus, but not to other regions. Glutamatergic, but not GABAergic, neurons in the lateral hypothalamus function as downstream neurons of AgRP neurons. Importantly, these neurons play a key role in modulating preferences for both appetitive and aversive tastes by using distinct pathways projecting to the lateral septum or the lateral habenula, respectively. Our results suggest that these hypothalamic circuits would be important for optimizing feeding behavior under fasting. Hunger modulates perception of good and bad tastes. Here, the authors report that orexigenic AgRP neurons in the hypothalamus mediate these effects through glutamatergic lateral hypothalamic neurons that send distinct projections to the lateral septum and lateral habenula.

The Drosophila tumour suppressors Scribbled and Discs large 1 are found to be essential regulators of planar spindle alignment during epithelial cell division; aberrant effects of spindle alignment are shown to be corrected through apoptosis, and the suppression of this mechanism can result in epithelial dysplasia and tumorigenesis. Discs large, Scribbled involved in spindle alignment Mitotic spindle formation is a key step towards the segregation of chromosomes into two daughter cells during mitosis, and the precise alignment of mitotic spindles to the plane of the epithelium is thought to be important in maintaining tissue integrity. The in vivo determinants of planar spindle orientation remain unknown. Here Matthew Gibson and colleagues demonstrate that the actomyosin cortex and junction-localized tumour suppressors Scribbled and Discs large 1 are essential regulators of planar spindle alignment. Defective alignment of the mitotic spindle correlates with cell delamination and apoptotic death, and furthermore, blocking death of misaligned cells is sufficient to drive the formation of tumour-like cell masses. The authors propose that the deleterious effects of aberrant spindle alignment are corrected by apoptosis and that suppression of this mechanism could result in epithelial dysplasia and tumorigenesis. During epithelial cell proliferation, planar alignment of the mitotic spindle coordinates the local process of symmetric cell cleavage with the global maintenance of polarized tissue architecture 1 , 2 . Although the disruption of planar spindle alignment is proposed to cause epithelial to mesenchymal transition and cancer 3 , 4 , 5 , 6 , the in vivo mechanisms regulating mitotic spindle orientation remain elusive. Here we demonstrate that the actomyosin cortex and the junction-localized neoplastic tumour suppressors Scribbled and Discs large 1 have essential roles in planar spindle alignment and thus the control of epithelial integrity in the Drosophila imaginal disc. We show that defective alignment of the mitotic spindle correlates with cell delamination and apoptotic death, and that blocking the death of misaligned cells is sufficient to drive the formation of basally localized tumour-like masses. These findings indicate a key role for junction-mediated spindle alignment in the maintenance of epithelial integrity, and also reveal a previously unknown cell-death-mediated tumour-suppressor function inherent in the polarized architecture of epithelia.

As the sister group to bilaterians, cnidarians stand in a unique phylogenetic position that provides insight into evolutionary aspects of animal development, physiology, and behavior. While cnidarians are classified into two types, sessile polyps and free-swimming medusae, most studies at the cellular and molecular levels have been conducted on representative polyp-type cnidarians and have focused on establishing techniques of genetic manipulation. Recently, gene knockdown by delivery of short hairpin RNAs into eggs via electroporation has been introduced in two polyp-type cnidarians, Nematostella vectensis and Hydractinia symbiolongicarpus , enabling systematic loss-of-function experiments. By contrast, current methods of genetic manipulation for most medusa-type cnidarians, or jellyfish, are quite limited, except for Clytia hemisphaerica , and reliable techniques are required to interrogate function of specific genes in different jellyfish species. Here, we present a method to knock down target genes by delivering small interfering RNA (siRNA) into fertilized eggs via electroporation, using the hydrozoan jellyfish, Clytia hemisphaerica and Cladonema paciificum . We show that siRNAs targeting endogenous GFP1 and Wnt3 in Clytia efficiently knock down gene expression and result in known planula phenotypes: loss of green fluorescence and defects in axial patterning, respectively. We also successfully knock down endogenous Wnt3 in Cladonema by siRNA electroporation, which circumvents the technical difficulty of microinjecting small eggs. Wnt3 knockdown in Cladonema causes gene expression changes in axial markers, suggesting a conserved Wnt/β-catenin-mediated pathway that controls axial polarity during embryogenesis. Our gene-targeting siRNA electroporation method is applicable to other animals, including and beyond jellyfish species, and will facilitate the investigation and understanding of myriad aspects of animal development.

Blastema formation is a crucial process that provides a cellular source for regenerating tissues and organs. While bilaterians have diversified blastema formation methods, its mechanisms in non-bilaterians remain poorly understood. Cnidarian jellyfish, or medusae, represent early-branching metazoans that exhibit complex morphology and possess defined appendage structures highlighted by tentacles with stinging cells (nematocytes). Here, we investigate the mechanisms of tentacle regeneration, using the hydrozoan jellyfish Cladonema pacificum . We show that proliferative cells accumulate at the tentacle amputation site and form a blastema composed of cells with stem cell morphology. Nucleoside pulse-chase experiments indicate that most repair-specific proliferative cells (RSPCs) in the blastema are distinct from resident stem cells. We further demonstrate that resident stem cells control nematogenesis and tentacle elongation during both homeostasis and regeneration as homeostatic stem cells, while RSPCs preferentially differentiate into epithelial cells in the newly formed tentacle, analogous to lineage-restricted stem/progenitor cells observed in salamander limbs. Taken together, our findings propose a regeneration mechanism that utilizes both resident homeostatic stem cells (RHSCs) and RSPCs, which in conjunction efficiently enable functional appendage regeneration, and provide novel insight into the diversification of blastema formation across animal evolution.

One of the most distinctive features of human sweet taste perception is its broad tuning to chemically diverse compounds ranging from low-molecular-weight sweeteners to sweet-tasting proteins. Many reports suggest that the human sweet taste receptor (hT1R2-hT1R3), a heteromeric complex composed of T1R2 and T1R3 subunits belonging to the class C G protein-coupled receptor family, has multiple binding sites for these sweeteners. However, it remains unclear how the same receptor recognizes such diverse structures. Here we aim to characterize the modes of binding between hT1R2-hT1R3 and low-molecular-weight sweet compounds by functional analysis of a series of site-directed mutants and by molecular modeling-based docking simulation at the binding pocket formed on the large extracellular amino-terminal domain (ATD) of hT1R2. We successfully determined the amino acid residues responsible for binding to sweeteners in the cleft of hT1R2 ATD. Our results suggest that individual ligands have sets of specific residues for binding in correspondence with the chemical structures and other residues responsible for interacting with multiple ligands.

Feeding is essential for survival and taste greatly influences our feeding behaviors. Palatable tastes such as sweet trigger feeding as a symbol of a calorie-rich diet containing sugar or proteins, while unpalatable tastes such as bitter terminate further consumption as a warning against ingestion of harmful substances. Therefore, taste is considered a criterion to distinguish whether food is edible. However, perception of taste is also modulated by physiological changes associated with internal states such as hunger or satiety. Empirically, during hunger state, humans find ordinary food more attractive and feel less aversion to food they usually dislike. Although functional magnetic resonance imaging studies performed in primates and in humans have indicated that some brain areas show state-dependent response to tastes, the mechanisms of how the brain senses tastes during different internal states are poorly understood. Recently, using newly developed molecular and genetic tools as well as in vivo imaging, researchers have identified many specific neuronal populations or neural circuits regulating feeding behaviors and taste perception process in the central nervous system. These studies could help us understand the interplay between homeostatic regulation of energy and taste perception to guide proper feeding behaviors.

Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including G s -linked GPCRs. At present, the potential role of G s -coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of G s -coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity. Hypothalamic Agouti-related peptide (AgRP) neurons play a key role in regulating food intake. Here, the authors report a novel pathway in which activation of Gs-coupled receptors on AgRP neurons leads to robust, sustained increase in food intake.

Background The remarkable regenerative abilities observed in planarians and cnidarians are closely linked to the active proliferation of adult stem cells and the precise differentiation of their progeny, both of which typically deteriorate during aging in low regenerative animals. While regeneration-specific genes conserved in highly regenerative organisms may confer regenerative abilities and long-term maintenance of tissue homeostasis, it remains unclear whether introducing these regenerative genes into low regenerative animals can improve their regeneration and aging processes. Results Here, we ectopically express highly regenerative species-specific JmjC domain-encoding genes (HRJDs) in Drosophila , a widely used low regenerative model organism. Surprisingly, HRJD expression impedes tissue regeneration in the developing wing disc but extends organismal lifespan when expressed in the intestinal stem cell lineages of the adult midgut under non-regenerative conditions. Notably, HRJDs enhance the proliferative activity of intestinal stem cells while maintaining their differentiation fidelity, ameliorating age-related decline in gut barrier functions. Conclusions These findings together suggest that the introduction of highly regenerative species-specific genes can improve stem cell functions and promote a healthy lifespan when expressed in aging animals.