Process Of Lateral Inhibition Research Articles

Novel Genome-Engineered H Alleles Differentially Affect Lateral Inhibition and Cell Dichotomy Processes during Bristle Organ Development.

Hairless (H) encodes the major antagonist in the Notch signaling pathway, which governs cellular differentiation of various tissues in Drosophila. By binding to the Notch signal transducer Suppressor of Hairless (Su(H)), H assembles repressor complexes onto Notch target genes. Using genome engineering, three new H alleles, HFA, HLLAA and HWA were generated and a phenotypic series was established by several parameters, reflecting the residual H-Su(H) binding capacity. Occasionally, homozygous HWA flies develop to adulthood. They were compared with the likewise semi-viable HNN allele affecting H-Su(H) nuclear entry. The H homozygotes were short-lived, sterile and flightless, yet showed largely normal expression of several mitochondrial genes. Typical for H mutants, both HWA and HNN homozygous alleles displayed strong defects in wing venation and mechano-sensory bristle development. Strikingly, however, HWA displayed only a loss of bristles, whereas bristle organs of HNN flies showed a complete shaft-to-socket transformation. Apparently, the impact of HWA is restricted to lateral inhibition, whereas that of HNN also affects the respective cell type specification. Notably, reduction in Su(H) gene dosage only suppressed the HNN bristle phenotype, but amplified that of HWA. We interpret these differences as to the role of H regarding Su(H) stability and availability.

Cell fate determination is influenced by Notch heterogeneity.

Notch signaling (NS) determines the fate of adjacent cells during metazoans development. This intercellular signaling mechanism regulates diverse development processes like cell differentiation, proliferation, survival and is considered responsible for maintaining cellular homeostasis. In this study, we elucidate the role of Notch heterogeneity (NH) in cell fate determination. We studied the role of NH at intercellular, intracellular and the coexistence of Notch variation simultaneously at the intracellular and intercellular level in direct cell-cell signaling on an irregular cell mosaic. In addition, the effect of intracellular Notch receptor diffusion on an irregular cell lattice is also taken into account during Delta-Notch lateral inhibition (LI) process. Through mathematical and computational models, we discovered that the classical checkerboard pattern formation can be reproduced with an accuracy of 70-81% by accounting for NH in a realistic epithelial layer of multicellular organisms.

Division of Labor: Roles of Groucho and CtBP in Notch-Mediated Lateral Inhibition that Controls Intestinal Stem Cell Differentiation in Drosophila.

SummaryIntestinal stem cell (ISC) differentiation in the Drosophila midgut requires Delta/Notch-mediated lateral inhibition, which separates the fate of ISCs from differentiating enteroblasts (EBs). Although a canonical Notch signaling cascade is involved in the lateral inhibition, its regulation at the transcriptional level is still unclear. Here we show that the establishment of lateral inhibition between ISC-EB requires two evolutionarily conserved transcriptional co-repressors Groucho (Gro) and C-terminal binding protein (CtBP) that act differently. Gro functions in EBs with E(spl)-C proteins to suppress Delta expression, inhibit cell-cycle re-entry, and promote cell differentiation, whereas CtBP functions specifically in ISCs to mediate transcriptional repression of Su(H) targets and maintain ISC fate. Interestingly, several E(spl)-C genes are also expressed in ISCs that cooperate with Gro to inhibit cell proliferation. Collectively, our study demonstrates separable and cell-type-specific functions of Gro and CtBP in a lateral inhibition process that controls the proliferation and differentiation of tissue stem cells.

On the Neural and Mechanistic Bases of Self-Control.

Intertemporal choice requires a dynamic interaction between valuation and deliberation processes. While evidence identifying candidate brain areas for each of these processes is well established, the precise mechanistic role carried out by each brain region is still debated. In this article, we present a computational model that clarifies the unique contribution of frontoparietal cortex regions to intertemporal decision making. The model we develop samples reward and delay information stochastically on a moment-by-moment basis. As preference for the choice alternatives evolves, dynamic inhibitory processes are executed by way of asymmetric lateral inhibition. We find that it is these lateral inhibition processes that best explain the contribution of frontoparietal regions to intertemporal decision making exhibited in our data.

Lateral Inhibition Map Updating Method to Prevent Map Deformation for Simultaneous Localization and Mapping in Natural Environment

In this paper, a novel real time map updating algorithm using a concept of lateral inhibition was proposed and it was evaluated by simple 2D mapping experiment. For long time and difficult map creation process of simultaneous localization and mapping (SLAM) algorithm, stable map updating is one of the important topics. By using the lateral inhibition process to the map updating process, it is able to reduce the complexity of the map updating process of the SLAM. It could reduce the noise around the wall and emphasize the border (such a wall). The experimental result of map updating process of 6.0 x 3.5 m 2D room with many obstacles shows the x-y positional and the rotational estimation precision would be measured as x,y= 1.8 ×10-6 m (less than the LIDAR measurement error about 0.04 m) and the = - 1.9×10-2 deg (1 hour measurement), and the map was updated real time when the LIDAR sensor was moving from a position to another room position with low speed. After the 38 min outdoor experiment, the occupancy map was stably maintained, and there is also slight rotation and position estimation errors (x,y = 0.0 m, = 8.3 ×10-2 deg). The proposed method could suppress the wall existence probability distribution creeping induced by the natural environment vibration such as tree or leaves.

Somatosensory lateral inhibition processes modulate motor response inhibition - an EEG source localization study

Motor inhibitory control is a central executive function, but only recently the importance of perceptual mechanisms for these processes has been focused. It is elusive whether basic mechanisms governing sensory perception affect motor inhibitory control. We examine whether sensory lateral inhibition (LI) processes modulate motor inhibitory control using a system neurophysiological approach combining EEG signal decomposition with source localization methods in a somatosensory GO/NOGO task. The results show that inter-individual variations in the strength of LI effects predominantly affect processes when information needs to be integrated between cerebral hemispheres. If information needs to be integrated between hemispheres, strong sensory suppression will lead to more impulsive errors. Importantly, the neurophysiological data suggest that not purely perceptual or motor processes are affected. Rather, LI affects the response selection level and modulates processes of stimulus categorization. This is associated with activity modulations in the posterior parietal cortex. The results suggest that when sensory suppression is high and when information needs to be integrated across hemispheres, these processes are less efficient, which likely leads to worse motor inhibitory control. The results show how basis principles modulating perceptual processes affect subsequent motor inhibitory control processes.

Proposal of Lateral Inhibition Real Time Map Updating Method for Simultaneous Localization and Mapping by Using LRF

In this paper, a novel real time map updating algorithm using a concept of lateral inhibition was proposed and it was evaluated by simple 2D room mapping experiment. For long time and difficult map creation process of simultaneous localization and mapping (SLAM) algorithm, stable map updating is one of the important topics. By using the lateral inhibition process to the map updating process, it is able to reduce the complexity of the map updating process of the SLAM. It could reduce the noise around the wall and emphasize the border (such a wall). The experimental result of 6.0 x 3.5 m 2D room with many obstacles shows the x-y positional and the rotational estimation precision would be measured as Δx, y= 0±0 m (within laser range finder measurement error, ±S.D.) and the θ= - 3.3×10-4 ±1.4×10-3 rad (1 hour measurement), and the map was updated real time when the laser range finder sensor was moving from a position to another room position with low speed. In addition, the environment map was created without deformation in the three trees environment which has a little wind (<1m/sec) and uneven shape. The long time stable position and rotation estimation could be realized by using the lateral inhibition mapping update algorithm.

Contrast Sensitivity and Lateral Inhibition Are Enhanced With Macular Carotenoid Supplementation.

Once deposited in the retina, the so-called macular carotenoids lutein (L), zeaxanthin (Z), and mesozeaxanthin (MZ) have been shown to enhance visual performance. The purpose of our study was to investigate whether increasing macular pigment optical density (MPOD) could enhance lateral inhibitory processes, and thereby improve contrast sensitivity (CS). A total of 59 young (18-25 years), healthy individuals participated in this 1-year, double-masked, placebo-controlled study. MPOD was assessed via heterochromatic flicker photometry. Lateral inhibition sensitivity (LIS) was determined with a computer-based, user-adjustable Hermann grid. CS (at 8 cycles/degree) was determined with a two-alternative, forced-choice procedure. Subjects received either the placebo (n = 10), 12 mg total macular carotenoids (n = 24), or 24 mg total macular carotenoids (n = 25). MPOD, LIS, and CS increased significantly in treatment groups between baseline and 6 months, and between 6 and 12 months (P < 0.05 for all) versus placebo. The relationships between changes in MPOD and both LIS and CS were significant at 6 and 12 months (P < 0.05 for both). Changes in CS and LIS over the 12-month study period were found to be significantly related (r = 0.41; P = 0.0014). Increases in MPOD led to enhanced lateral inhibitory processes, which correspond to improved CS. Because optical filtering has the same net effect on dark versus light bars, it cannot explain these improvements. Improvement in CS with increases in MPOD therefore appears to involve enhancement of the fundamental physiological systems that give rise to edge detection.

Cell-Cell Contact Area Affects Notch Signaling and Notch-Dependent Patterning

SummaryDuring development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from microns to tens of microns. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes.

The Notch pathway in the annelid Platynereis: insights into chaetogenesis and neurogenesis processes.

Notch is a key signalling pathway playing multiple and varied functions during development. Notch regulates the selection of cells with a neurogenic fate and maintains a pool of yet uncommitted precursors through lateral inhibition, both in insects and in vertebrates. Here, we explore the functions of Notch in the annelid Platynereis dumerilii (Lophotrochozoa). Conserved components of the pathway are identified and a scenario for their evolution in metazoans is proposed. Unexpectedly, neither Notch nor its ligands are expressed in the neurogenic epithelia of the larva at the time when massive neurogenesis begins. Using chemical inhibitors and neural markers, we demonstrate that Notch plays no major role in the general neurogenesis of larvae. Instead, we find Notch components expressed in nascent chaetal sacs, the organs that produce the annelid bristles. Impairing Notch signalling induces defects in chaetal sac formation, abnormalities in chaetae producing cells and a change of identity of chaeta growth accessory cells. This is the first bilaterian species in which the early neurogenesis processes appear to occur without a major involvement of the Notch pathway. Instead, Notch is co-opted to pattern annelid-specific organs, likely through a lateral inhibition process. These features reinforce the view that Notch signalling has been recruited multiple times in evolution due to its remarkable ‘toolkit’ nature.

Seeing without knowing: Operational principles along the early visual pathway

Single cases may lead to unexpected hypotheses in psychology. We retrospectively analyzed single case studies that suggested organizational principles along the early visual pathway, which have remained unanswered until now. In spite of the inhomogeneity of sensitivity, paradoxically the visual field on the subjective level appears to be homogeneous; constancy of brightness of supra-threshold stimuli throughout the visual field is claimed to be responsible for homogeneity; specific summation properties of retinal ganglion cells are hypothesized to guarantee this effect. With a brain-injured patient having suffered a partial visual field loss it can be shown that color induction is a retinal phenomenon; lateral inhibitory processes at the level of amacrine cells are hypothesized as neural network. Third case: In a patient having suffered a bilateral occipital lobe infarction, some functional recovery has been demonstrated; divergence and convergence of projection in the ascending neural pathway are suggested as a structural basis for recovery. Slowed down binocular rivalry discloses a sequential mechanism in the construction of a visual percept. Fourth case: The pre-wired projection of the retina to the visual cortex in spite of a severe squint of one eye is confirmed, but paradoxically some local neuroplasticity is also suggested. Fifth case: Using habituation of local sensitivity in the visual field and its resetting by interhemispheric interactions as an experimental paradigm, it is suggested that spatial attention is controlled at the midbrain level. Sixth case: Observations on residual vision or "blindsight" support the hypothesis that the visual cortex is the one and only structure responsible for visual perception on a conscious level. The unifying principle of these retrospective analyses is that subjective visual phenomena can lead to unexpected but testable hypotheses of neural processing on the structural and functional level in the early visual pathway.

Stem cell and progenitor fate in the mammalian intestine: Notch and lateral inhibition in homeostasis and disease.

The control of cell fate decisions is vital to build functional organs and maintain normal tissue homeostasis, and many pathways and processes cooperate to direct cells to an appropriate final identity. Because of its continuously renewing state and its carefully organised hierarchy, the mammalian intestine has become a powerful model to dissect these pathways in health and disease. One of the signalling pathways that is key to maintaining the balance between proliferation and differentiation in the intestinal epithelium is the Notch pathway, most famous for specifying distinct cell fates in adjacent cells via the evolutionarily conserved process of lateral inhibition. Here, we will review recent discoveries that advance our understanding of how cell fate in the mammalian intestine is decided by Notch and lateral inhibition, focusing on the molecular determinants that regulate protein turnover, transcriptional control and epigenetic regulation.

Lateral inhibition of Notch signaling in neoplastic cells.

During normal development, heterogeneous expression of Notch ligands can result in pathway suppression in the signal-sending cell, a process known as lateral inhibition. It is unclear if an analogous phenomenon occurs in malignant cells. We observed significant induction of Notch ligands in glioblastoma neurospheres and pancreatic carcinoma cells cultured in low oxygen, suggesting that this phenomenon could occur around hypoxic regions. To model lateral inhibition in these tumors, the ligand Jagged1 was overexpressed in glioblastoma and pancreatic carcinoma cells, resulting in overall induction of pathway targets. However, when ligand high and ligand low cells from a single line were co-cultured and then separated, we noted suppression of Notch pathway targets in the former and induction in the latter, suggesting that neoplastic lateral inhibition can occur. We also found that repression of Notch pathway targets in signal-sending cells may occur through the activity of a Notch ligand intracellular domain, which translocates into the nucleus. Understanding how this neoplastic lateral inhibition process functions in cancer cells may be important in targeting ligand driven Notch signaling in solid tumors.

Parallel developmental genetic features underlie stickleback gill raker evolution

BackgroundConvergent evolution, the repeated evolution of similar phenotypes in independent lineages, provides natural replicates to study mechanisms of evolution. Cases of convergent evolution might have the same underlying developmental and genetic bases, implying that some evolutionary trajectories might be predictable. In a classic example of convergent evolution, most freshwater populations of threespine stickleback fish have independently evolved a reduction of gill raker number to adapt to novel diets. Gill rakers are a segmentally reiterated set of dermal bones important for fish feeding. A previous large quantitative trait locus (QTL) mapping study using a marine × freshwater F2 cross identified QTL on chromosomes 4 and 20 with large effects on evolved gill raker reduction.ResultsBy examining skeletal morphology in adult and developing sticklebacks, we find heritable marine/freshwater differences in gill raker number and spacing that are specified early in development. Using the expression of the Ectodysplasin receptor (Edar) gene as a marker of raker primordia, we find that the differences are present before the budding of gill rakers occurs, suggesting an early change to a lateral inhibition process controlling raker primordia spacing. Through linkage mapping in F2 fish from crosses with three independently derived freshwater populations, we find in all three crosses QTL overlapping both previously identified QTL on chromosomes 4 and 20 that control raker number. These two QTL affect the early spacing of gill raker buds.ConclusionsCollectively, these data demonstrate that parallel developmental genetic features underlie the convergent evolution of gill raker reduction in freshwater sticklebacks, suggesting that even highly polygenic adaptive traits can have a predictable developmental genetic basis.

Inner retinal inhibition shapes the receptive field of retinal ganglion cells in primate

The centre–surround organisation of receptive fields is a feature of most retinal ganglion cells (RGCs) and is critical for spatial discrimination and contrast detection. Although lateral inhibitory processes are known to be important in generating the receptive field surround, the contribution of each of the two synaptic layers in the primate retina remains unclear. Here we studied the spatial organisation of excitatory and inhibitory synaptic inputs onto ON and OFF ganglion cells in the primate retina. All RGCs showed an increase in excitation in response to stimulus of preferred polarity. Inhibition onto RGCs comprised two types of responses to preferred polarity: some RGCs showed an increase in inhibition whilst others showed removal of tonic inhibition. Excitatory inputs were strongly spatially tuned but inhibitory inputs showed more variable organisation: in some neurons they were as strongly tuned as excitation, and in others inhibitory inputs showed no spatial tuning. We targeted one source of inner retinal inhibition by functionally ablating spiking amacrine cells with bath application of tetrodotoxin (TTX). TTX significantly reduced the spatial tuning of excitatory inputs. In addition, TTX reduced inhibition onto those RGCs where a stimulus of preferred polarity increased inhibition. Reconstruction of the spatial tuning properties by somatic injection of excitatory and inhibitory synaptic conductances verified that TTX-mediated inhibition onto bipolar cells increases the strength of the surround in RGC spiking output. These results indicate that in the primate retina inhibitory mechanisms in the inner plexiform layer sharpen the spatial tuning of ganglion cells.

The Insulin Receptor Is Required for the Development of the Drosophila Peripheral Nervous System

The Insulin Receptor (InR) in Drosophila presents features conserved in its mammalian counterparts. InR is required for growth; it is expressed in the central and embryonic nervous system and modulates the time of differentiation of the eye photoreceptor without altering cell fate. We show that the InR is required for the formation of the peripheral nervous system during larval development and more particularly for the formation of sensory organ precursors (SOPs) on the fly notum and scutellum. SOPs arise in the proneural cluster that expresses high levels of the proneural proteins Achaete (Ac) and Scute (Sc). The other cells will become epidermis due to lateral inhibition induced by the Notch (N) receptor signal that prevents its neighbors from adopting a neural fate. In addition, misexpression of the InR or of other components of the pathway (PTEN, Akt, FOXO) induces the development of an abnormal number of macrochaetes that are Drosophila mechanoreceptors. Our data suggest that InR regulates the neural genes ac, sc and sens. The FOXO transcription factor which is localized in the cytoplasm upon insulin uptake, displays strong genetic interaction with the InR and is involved in Ac regulation. The genetic interactions between the epidermal growth factor receptor (EGFR), Ras and InR/FOXO suggest that these proteins cooperate to induce neural gene expression. Moreover, InR/FOXO is probably involved in the lateral inhibition process, since genetic interactions with N are highly significant. These results show that the InR can alter cell fate, independently of its function in cell growth and proliferation.

Fbw7 Repression by Hes5 Creates a Feedback Loop That Modulates Notch-Mediated Intestinal and Neural Stem Cell Fate Decisions

Author SummaryThe Notch signalling pathway is a highly conserved system that controls cell differentiation decisions in a wide range of animal species and cell types, and at different steps during cell lineage progression. An important function of the Notch pathway is in lateral inhibition—an interaction between equal adjacent cells that drives them towards different final states. The basic principle of lateral inhibition is that activation of the Notch cell surface receptor represses production of the Notch ligand (also borne on the cell surface). Consequently, cells expressing less Notch produce more Notch ligand that can activate the Notch pathway in neighboring cells and thereby amplify the differences between these cells. However, the additional regulatory circuits required to fine-tune this delicate process have so far remained elusive. Here we describe the identification of a novel intracellular positive feedback loop that connects Fbw7 (the ubiquitin ligase responsible for targeting Notch for degradation) and Notch itself. We show that Fbw7 reduces the stability of Notch intracellular domain (NICD) protein, as previously established, but also that the fbw7 gene is itself transcriptionally downregulated by the Notch effector Hes5. Thus we conclude that increased Notch activity causes NICD stabilisation. Further, we demonstrate that perturbation of this regulatory loop is responsible for the Fbw7 haploinsufficiency observed for Notch-dependent functions in intestine and brain stem cells.

Regulation of neuronal differentiation at the neurogenic wavefront

Signaling mediated by the Delta/Notch system controls the process of lateral inhibition, known to regulate neurogenesis in metazoans. Lateral inhibition takes place in equivalence groups formed by cells having equal capacity to differentiate, and it results in the singling out of precursors, which subsequently become neurons. During normal development, areas of active neurogenesis spread through non-neurogenic regions in response to specific morphogens, giving rise to neurogenic wavefronts. Close contact of these wavefronts with non-neurogenic cells is expected to affect lateral inhibition. Therefore, a mechanism should exist in these regions to prevent disturbances of the lateral inhibitory process. Focusing on the developing chick retina, we show that Dll1 is widely expressed by non-neurogenic precursors located at the periphery of this tissue, a region lacking Notch1, lFng, and differentiation-related gene expression. We investigated the role of this Dll1 expression through mathematical modeling. Our analysis predicts that the absence of Dll1 ahead of the neurogenic wavefront results in reduced robustness of the lateral inhibition process, often linked to enhanced neurogenesis and the presence of morphological alterations of the wavefront itself. These predictions are consistent with previous observations in the retina of mice in which Dll1 is conditionally mutated. The predictive capacity of our mathematical model was confirmed further by mimicking published results on the perturbation of morphogenetic furrow progression in the eye imaginal disc of Drosophila. Altogether, we propose that Notch-independent Delta expression ahead of the neurogenic wavefront is required to avoid perturbations in lateral inhibition and wavefront progression, thus optimizing the neurogenic process.

Abstract 3335: The potential role of lateral inhibition in the maintenance of glioblastoma cancer stem cells

Abstract Glioblastoma (GBM) is a malignant cancer of the central nervous system. Tumor cells are highly resistant to conventional therapies and tumors always recur. Cancer stem cells are thought to be critical for long-term growth and therapeutic resistance of GBM. It is therefore important to understand the signaling mechanisms maintaining GBM cancer stem cells. Notch is known to be an important signaling pathway during neural development, and can promote the maintenance of stem and progenitor cells via the process of lateral inhibition. Lateral inhibition is a contact-dependent signaling mechanism by which some cells within a field remain stem-like while others differentiate. In normal development, Notch ligands initiate this process by binding to the receptor on an adjacent cell, signaling to this neighbor to remain undifferentiated. Although Notch is known to be a critical player in the maintenance of stem-like cancer cells in various tumor types, including GBM, it is not known if the mechanism of lateral inhibition is also conserved in neural cancer stem cells. To test this hypothesis, we engineered a model system where isogenic cells expressing low and high levels of the Jag1 ligand are co-cultured followed by flow-based separation and determination of Notch pathway activity in each respective population. These experiments suggest that lateral inhibition is conserved in GBM. In the GBM neurosphere lines HSR-GBM1 and 040821, co-culture induced expression of Notch targets Hes5 and Hey1 in Jag1-low “signal receiving” cells and inhibited expression of these targets in Jag1-overexpressing “signal sending” isogenic cells. Preliminary experiments suggest that the ligand intracellular domain (ICD) is involved in this process. Our data suggest conservation of a developmental mechanism regulating Notch activation in cancer, and may affect our understanding of how to treat Notch-dependent tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3335. doi:1538-7445.AM2012-3335

Vision of the Body Modulates Somatosensory Intracortical Inhibition

The magnitude of somatosensory evoked potentials (SEPs) elicited by simultaneous electrical stimulation of adjacent digits is generally less than the sum of potentials evoked by stimulation of each digit individually. This under-additivity suggests suppression between representations of adjacent skin regions and may reflect a process of lateral inhibition by interneurons in somatosensory cortex. Given that simply viewing the body enhances tactile acuity and that tactile acuity depends on cortical lateral inhibition, we investigated how viewing the body modulates suppressive interactions between simultaneous afferent volleys from adjacent fingers. We recorded SEPs evoked by electrical stimulation of the right index and middle fingers, either individually or simultaneously, while participants viewed either their own hand or an object. In between trains of electrical stimuli, participants discriminated the orientation of tactile gratings applied to either finger. Consistent with previous findings, viewing the hand enhanced tactile acuity. Furthermore, viewing the hand increased the suppression of the P50 potential due to simultaneous electrical stimulation of both fingers. Moreover, the visual enhancement of tactile performance correlated across participants with the visual modulation of suppression. These results demonstrate that vision enhances somatosensation by modulating activity of inhibitory interneuronal circuits in the somatosensory cortex.