The signals that induce the organ of Corti and define its boundaries in the cochlea are poorly understood. We show that two Notch modifiers, Lfng and Mfng, are transiently expressed precisely at the neural boundary of the organ of Corti. Cre-Lox fate mapping shows this region gives rise to inner hair cells and their associated inner phalangeal cells. Mutation of Lfng and Mfng disrupts this boundary, producing unexpected duplications of inner hair cells and inner phalangeal cells. This phenotype is mimicked by other mouse mutants or pharmacological treatments that lower but not abolish Notch signaling. However, strong disruption of Notch signaling causes a very different result, generating many ectopic hair cells at the expense of inner phalangeal cells. Our results show that Notch signaling is finely calibrated in the cochlea to produce precisely tuned levels of signaling that first set the boundary of the organ of Corti and later regulate hair cell development.DOI: http://dx.doi.org/10.7554/eLife.19921.001

Significance Adult hippocampal neurogenesis underpins learning, memory, and mood but diminishes with age and certain illnesses. The orphan nuclear receptor TLX/NR2E1 regulates neural stem and progenitor cell self-renewal and proliferation, but its orphan status has hindered its utilization as a therapeutic target to modulate adult neurogenesis. Here, we deorphanize TLX and report that oleic acid is an endogenous, metabolic ligand of TLX. These findings open avenues for future therapeutic modulation of TLX to counteract cognitive and mental decline in aging and diseases associated with decreased neurogenesis.

Hippocampal neural stem cells (NSCs) integrate inputs from multiple sources to balance quiescence and activation. Notch signaling plays a key role during this process. Here, we report that Lunatic fringe (Lfng), a key modifier of the Notch receptor, is selectively expressed in NSCs. Further, Lfng in NSCs and Notch ligands Delta1 and Jagged1, expressed by their progeny, together influence NSC recruitment, cell cycle duration, and terminal fate. We propose a new model in which Lfng-mediated Notch signaling enables direct communication between a NSC and its descendants, so that progeny can send feedback signals to the ‘mother’ cell to modify its cell cycle status. Lfng-mediated Notch signaling appears to be a key factor governing NSC quiescence, division, and fate.DOI: http://dx.doi.org/10.7554/eLife.24660.001

The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells (NSCs), are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associated cognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has garnered significant interest because targeting it could be a novel potential therapeutic strategy for these disorders. However, if we are to use neurogenesis to halt or reverse hippocampal-related pathology, we need to understand better the core molecular machinery that governs NSC and their progeny. In this review, we summarize a wide variety of mouse models used in adult neurogenesis field, present their advantages and disadvantages based on specificity and efficiency of labeling of different cell types, and review their contribution to our understanding of the biology and the heterogeneity of different cell types found in adult neurogenic niches.

BackgroundThe mammalian brain is organized into regions with specific biological functions and properties. These regions have distinct transcriptomes, but little is known whether they may also differ in their metabolome. The metabolome, a collection of small molecules or metabolites, is at the intersection of the genetic background of a given cell or tissue and the environmental influences that affect it. Thus, the metabolome directly reflects information about the physiologic state of a biological system under a particular condition. The objective of this study was to investigate whether various brain regions have diverse metabolome profiles, similarly to their genetic diversity. The answer to this question would suggest that not only the genome but also the metabolome may contribute to the functional diversity of brain regions.MethodsWe investigated the metabolome of four regions of the mouse brain that have very distinct functions: frontal cortex, hippocampus, cerebellum, and olfactory bulb. We utilized gas- and liquid- chromatography mass spectrometry platforms and identified 215 metabolites.ResultsPrincipal component analysis, an unsupervised multivariate analysis, clustered each brain region based on its metabolome content, thus providing the unique metabolic profile of each region. A pathway-centric analysis indicated that olfactory bulb and cerebellum had most distinct metabolic profiles, while the cortical parenchyma and hippocampus were more similar in their metabolome content. Among the notable differences were distinct oxidative-anti-oxidative status and region-specific lipid profiles. Finally, a global metabolic connectivity analysis using the weighted correlation network analysis identified five hub metabolites that organized a unique metabolic network architecture within each examined brain region. These data indicate the diversity of global metabolome corresponding to specialized regional brain function and provide a new perspective on the underlying properties of brain regions.ConclusionIn summary, we observed many differences in the metabolome among the various brain regions investigated. All four brain regions in our study had a unique metabolic signature, but the metabolites came from all categories and were not pathway-centric.Electronic supplementary materialThe online version of this article (10.1186/s12918-018-0644-0) contains supplementary material, which is available to authorized users.

Notch signalling maintains stem cell regeneration at the mouse intestinal crypt base and balances the absorptive and secretory lineages in the upper crypt and villus. Here we report the role of Fringe family of glycosyltransferases in modulating Notch activity in the two compartments. At the crypt base, RFNG is enriched in the Paneth cells and increases cell surface expression of DLL1 and DLL4. This promotes Notch activity in the neighbouring Lgr5+ stem cells assisting their self-renewal. Expressed by various secretory cells in the upper crypt and villus, LFNG promotes DLL surface expression and suppresses the secretory lineage . Hence, in the intestinal epithelium, Fringes are present in the ligand-presenting ‘sender’ secretory cells and promote Notch activity in the neighbouring ‘receiver’ cells. Fringes thereby provide for targeted modulation of Notch activity and thus the cell fate in the stem cell zone, or the upper crypt and villus.

BackgroundAdult hippocampal neurogenesis, the process of formation of new neurons, occurs throughout life in the hippocampus. New neurons have been associated with learning and memory as well as mood control, and impaired neurogenesis has been linked to depression, schizophrenia, autism and cognitive decline during aging. Thus, understanding the biological properties of adult neurogenesis has important implications for human health. Computational models of neurogenesis have attempted to derive biologically relevant knowledge, hard to achieve using experimentation. However, the majority of the computational studies have predominantly focused on the late stages of neurogenesis, when newborn neurons integrate into hippocampal circuitry. Little is known about the early stages that regulate proliferation, differentiation, and survival of neural stem cells and their immediate progeny.ResultsHere, based on the branching process theory and biological evidence, we developed a computational model that represents the early stage hippocampal neurogenic cascade and allows prediction of the overall efficiency of neurogenesis in both normal and diseased conditions. Using this stochastic model with a simulation program, we derived the equilibrium distribution of cell population and simulated the progression of the neurogenic cascade. Using BrdU pulse-and-chase experiment to label proliferating cells and their progeny in vivo, we quantified labeled newborn cells and fit the model on the experimental data. Our simulation results reveal unknown but meaningful biological parameters, among which the most critical ones are apoptotic rates at different stages of the neurogenic cascade: apoptotic rates reach maximum at the stage of neuroblasts; the probability of neuroprogenitor cell renewal is low; the neuroblast stage has the highest temporal variance within the cell types of the neurogenic cascade, while the apoptotic stage is short.ConclusionAt a practical level, the stochastic model and simulation framework we developed will enable us to predict overall efficiency of hippocampal neurogenesis in both normal and diseased conditions. It can also generate predictions of the behavior of the neurogenic system under perturbations such as increase or decrease of apoptosis due to disease or treatment.

Adult hippocampal neurogenesis underpins learning, memory, and mood, but diminishes with age and illness. The orphan nuclear receptor TLX/NR2E1 is known to regulate neural stem and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is unknown. We found that neural stem and progenitor cells require monounsaturated fatty acids to survive and proliferate. Specifically, oleic acid (18:1ω9) binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell cycle and neurogenesis genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation. These findings pave the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis.