Roles of Eph/ephrin bidirectional signaling during injury and recovery of the central nervous system

Multiple cellular components, including neuronal, glial and endothelial ceils, are involved in the sophis- ticated pathological processes following central nervous system injury. The pathological process cannot reduce damage or improve functional recovery by merely targeting the molecular mechanisms of neuronal cell death after central nerve system injuries. Eph receptors and ephrin ligands have drawn wide attention since the discovery of their extensive distribution and unique bidirectional signaling between astrocytes and neurons. The roles of Eph/ephrin bidirectional signaling in the developmental processes have been re- ported in previous research. Recent observations suggest that Eph/ephrin bidirectional signaling continues to be expressed in most regions and cell types in the adult central nervous system, playing diverse roles. The Eph/ephrin complex mediates neurogenesis and angiogenesis, promotes glial scar formation, regulates endocrine levels, inhibits myelin formation and aggravates inflammation and nerve pain caused by injury. ~lhe interaction between Eph and ephrin is also considered to be the key to angiogenesis. This review focus- es on the roles of Eph/ephrin bidirectional signaling in the repair of central nervous system injuries.

Promoting axon regeneration in the central nervous system by increasing PI3-kinase signaling

Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous system.Axons in the central nervous system fail to regenerate,meaning that injuries or diseases that cause loss of axonal connectivity have life-changing consequences.In 2008,genetic deletion of PTEN was identified as a means of stimulating robust regeneration in the optic nerve.PTEN is a phosphatase that opposes the actions of PI3-kinase,a family of enzymes that function to generate the membrane phospholipid PIP_(3) from PIP_(2)(phosphatidylinositol(3,4,5)-trisphosphate from phosphatidylinositol(4,5)-bisphosphate).Deletion of PTEN therefore allows elevated signaling downstream of PI3-kinase,and was initially demonstrated to promote axon regeneration by signaling through mTOR.More recently,additional mechanisms have been identified that contribute to the neuron-intrinsic control of regenerative ability.This review describes neuronal signaling pathways downstream of PI3-kinase and PIP3,and considers them in relation to both developmental and regenerative axon growth.We briefly discuss the key neuron-intrinsic mechanisms that govern regenerative ability,and describe how these are affected by signaling through PI3-kinase.We highlight the recent finding of a developmental decline in the generation of PIP_(3) as a key reason for regenerative failure,and summarize the studies that target an increase in signaling downstream of PI3-kinase to facilitate regeneration in the adult central nervous system.Finally,we discuss obstacles that remain to be overcome in order to generate a robust strategy for repairing the injured central nervous system through manipulation of PI3-kinase signaling.

Lactate metabolism in neurodegenerative diseases

Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.

NECAB family of neuronal calcium-binding proteins in health and disease

The N-terminal EF-hand calcium-binding proteins 1–3(NECAB1–3) constitute a family of predominantly neuronal proteins characterized by the presence of at least one EF-hand calcium-binding domain and a functionally less well characterized C-terminal antibiotic biosynthesis monooxygenase domain. All three family members were initially discovered due to their interactions with other proteins. NECAB1 associates with synaptotagmin-1, a critical neuronal protein involved in membrane trafficking and synaptic vesicle exocytosis. NECAB2 interacts with predominantly striatal G-protein-coupled receptors, while NECAB3 partners with amyloid-β A4 precursor protein-binding family A members 2 and 3, key regulators of amyloid-β production. This demonstrates the capacity of the family for interactions with various classes of proteins. NECAB proteins exhibit distinct subcellular localizations: NECAB1 is found in the nucleus and cytosol, NECAB2 resides in endosomes and the plasma membrane, and NECAB3 is present in the endoplasmic reticulum and Golgi apparatus. The antibiotic biosynthesis monooxygenase domain, an evolutionarily ancient component, is akin to atypical heme oxygenases in prokaryotes but is not wellcharacterized in vertebrates. Prokaryotic antibiotic biosynthesis monooxygenase domains typically form dimers, suggesting that calcium-mediated conformational changes in NECAB proteins may induce antibiotic biosynthesis monooxygenase domain dimerization, potentially activating some enzymatic properties. However, the substrate for this enzymatic activity remains uncertain. Alternatively, calcium-mediated conformational changes might influence protein interactions or the subcellular localization of NECAB proteins by controlling the availability of protein–protein interaction domains situated between the EF hands and the antibiotic biosynthesis monooxygenase domain. This review summarizes what is known about genomic organization, tissue expression, intracellular localization, interaction partners, and the physiological and pathophysiological role of the NECAB family.

PKHD1L1 blocks the malignant behavior of lung adenocarcinoma cells and restricts tumor growth by regulating CBX7

Objective:To explore the role of polycystic kidney and hepatic disease 1-like 1(PKHD1L1)in lung adenocarcinoma(LUAD).Methods:Bioinformatics tools were utilized to examine the clinical profile of PKHD1L1 and chromobox protein homolog 7(CBX7)in LUAD.The Cell Counting Kit-8,colony formation,terminal deoxynucleotidyl transferase dUTP nick end labeling,Transwell,and wound-healing assays were carried out to assess the proliferative,apoptotic,invasive,and migrative capacities of the cells.Furthermore,the interrelation between PKHD1L1 and CBX7 was validated using a co-immunoprecipitation assay.A LUAD mice model was constructed by subcutaneous injection of A549 cells.Finally,immunohistochemical staining was performed to evaluate CBX7 and Ki67 expression.Results:PKHD1L1 was downregulated in LUAD and predicted dismal outcomes in patients with LUAD.PKHD1L1 upregulation repressed the proliferative,invasive,and migrative capabilities of A549 cells and exacerbated the apoptotic rate.Additionally,PKHD1L1 may bind to CBX7 and positively modulate CBX7 expression.CBX7 deletion partly abrogated the effects of PKHD1L1 upregulation on the cellular biological activities in A549 cells.Furthermore,the PKHD1L1/CBX7 axis regulates the Hippo signaling pathway in A549 cells.PKHD1L1 restricted tumor growth in LUAD xenograft mice;this was partly abolished by CBX7 knockdown.Conclusion:PKHD1L1 can hinder LUAD progression by regulating CBX7-mediated Hippo signaling.

Glutamate receptors and glutamatergic signalling in the peripheral nerves

In the peripheral nervous system,the vast majority of axons are accommodated within the fibre bundles that constitute the peripheral nerves.Axons within the nerves are in close contact with myelinating glia,the Schwann cells that are ideally placed to respond to,and possibly shape,axonal activity.The mechanisms of intercellular communication in the peripheral nerves may involve direct contact between the cells,as well as signalling via diffusible substances.Neurotransmitter glutamate has been proposed as a candidate extracellular molecule mediating the cross-talk between cells in the peripheral nerves.Two types of experimental findings support this idea:first,glutamate has been detected in the nerves and can be released upon electrical or chemical stimulation of the nerves;second,axons and Schwann cells in the peripheral nerves express glutamate receptors.Yet,the studies providing direct experimental evidence that intercellular glutamatergic signalling takes place in the peripheral nerves during physiological or pathological conditions are largely missing.Remarkably,in the central nervous system,axons and myelinating glia are involved in glutamatergic signalling.This signalling occurs via different mechanisms,the most intriguing of which is fast synaptic communication between axons and oligodendrocyte precursor cells.Glutamate receptors and/or synaptic axon-glia signalling are involved in regulation of proliferation,migration,and differentiation of oligodendrocyte precursor cells,survival of oligodendrocytes,and re-myelination of axons after damage.Does synaptic signalling exist between axons and Schwann cells in the peripheral nerves?What is the functional role of glutamate receptors in the peripheral nerves?Is activation of glutamate receptors in the nerves beneficial or harmful during diseases?In this review,we summarise the limited information regarding glutamate release and glutamate receptors in the peripheral nerves and speculate about possible mechanisms of glutamatergic signalling in the nerves.We highlight the necessity of further research on this topic because it should help to understand the mechanisms of peripheral nervous system development and nerve regeneration during diseases.

Enteric nervous system and inflammatory bowel diseases:Correlated impacts and therapeutic approaches through the P2X7 receptor

The enteric nervous system(ENS)consists of thousands of small ganglia arranged in the submucosal and myenteric plexuses,which can be negatively affected by Crohn’s disease and ulcerative colitis-inflammatory bowel diseases(IBDs).IBDs are complex and multifactorial disorders characterized by chronic and recurrent inflammation of the intestine,and the symptoms of IBDs may include abdominal pain,diarrhea,rectal bleeding,and weight loss.The P2X7 receptor has become a promising therapeutic target for IBDs,especially owing to its wide expression and,in the case of other purinergic receptors,in both human and model animal enteric cells.However,little is known about the actual involvement between the activation of the P2X7 receptor and the cascade of subsequent events and how all these activities associated with chemical signals interfere with the functionality of the affected or treated intestine.In this review,an integrated view is provided,correlating the structural organization of the ENS and the effects of IBDs,focusing on cellular constituents and how therapeutic approaches through the P2X7 receptor can assist in both protection from damage and tissue preservation.

Muse cells decrease the neuroinflammatory response by modulating the proportion of M1 and M2 microglia in vitro

Neuroinflammation hinders repair of the central nervous system(CNS).Stem cell transplantation is a very promising approach for treatment of CNS injuries.However,it is difficult to select seed cells that can both facilitate nerve regeneration and improve the microenvironment in the CNS.In this study,we isolated multilineage-differentiating stress-enduring(Muse)cells from bone marrow mesenchymal stem cells.We explored the anti-inflammatory effect and mechanism of Muse cells in vitro by coculture of Muse cells with lipopolysaccharide-stimulated microglia.Our results showed that Muse cells effectively reduced the transcription and secretion of tumor necrosis factorαand interleukin-1βand increased the expression of transforming growth factor-βand interleukin-10 in microglia.In addition,Muse cells decreased the number of M1 microglia and increased the proportion of M2 microglia in an inflammatory environment more effectively than bone marrow mesenchymal stem cells.We also show that Muse cells inhibited the protein expression of toll-like receptor 4(TLR4)and myeloid differentiation primary response protein(MyD88)and inhibited the expression of the phosphorylated forms of transcription factor p65,nuclear factor(NF)-κB inhibitor alpha,and p38 mitogen-activated protein kinase(MAPK)in microglia.Therefore,we suggest Muse cells cause antineuroinflammatory effects by inhibition of the TLR4/MyD88/NF-κB and p38 MAPK signaling pathways in microglia.Our results shed light on the function of Muse cells in relation to CNS diseases and provide insight into the selection of seed cells.

Immortalized hippocampal astrocytes from 3xTg-AD mice,a new model to study disease-related astrocytic dysfunction:a comparative review

Alzheimer's disease(AD)is characterized by complex etiology,long-lasting pathogenesis,and celltype-specific alterations.Currently,there is no cure for AD,emphasizing the urgent need for a comprehensive understanding of cell-specific pathology.Astrocytes,principal homeostatic cells of the central nervous system,are key players in the pathogenesis of neurodegenerative diseases,including AD.Cellular models greatly facilitate the investigation of cell-specific pathological alterations and the dissection of molecular mechanisms and pathways.Tumor-derived and immortalized astrocytic cell lines,alongside the emerging technology of adult induced pluripotent stem cells,are widely used to study cellular dysfunction in AD.Surprisingly,no stable cell lines were available from genetic mouse AD models.Recently,we established immortalized hippocampal astroglial cell lines from amyloid-βprecursor protein/presenilin-1/Tau triple-transgenic(3xTg)-AD mice(denominated as wild type(WT)-and 3Tg-iAstro cells)using retrovirus-mediated transduction of simian virus 40 large T-antigen and propagation without clonal selection,thereby maintaining natural heterogeneity of primary cultures.Several groups have successfully used 3Tg-iAstro cells for single-cell and omics approaches to study astrocytic AD-related alterations of calcium signaling,mitochondrial dysfunctions,disproteostasis,altered homeostatic and signaling support to neurons,and blood-brain barrier models.Here we provide a comparative overview of the most used models to study astrocytes in vitro,such as primary culture,tumor-derived cell lines,immortalized astroglial cell lines,and induced pluripotent stem cell-derived astrocytes.We conclude that immortalized WT-and 3Tg-iAstro cells provide a noncompetitive but complementary,low-cost,easy-to-handle,and versatile cellular model for dissection of astrocyte-specific AD-related alterations and preclinical drug discovery.

Study of the roles of caspase-3 and nuclear factor kappa B in myenteric neurons in a P2X7 receptor knockout mouse model of ulcerative colitis

BACKGROUND The literature indicates that the enteric nervous system is affected in inflammatory bowel diseases(IBDs)and that the P2X7 receptor triggers neuronal death.However,the mechanism by which enteric neurons are lost in IBDs is unknown.AIM To study the role of the caspase-3 and nuclear factor kappa B(NF-κB)pathways in myenteric neurons in a P2X7 receptor knockout(KO)mouse model of IBDs.METHODS Forty male wild-type(WT)C57BL/6 and P2X7 receptor KO mice were euthanized 24 h or 4 d after colitis induction by 2,4,6-trinitrobenzene sulfonic acid(colitis group).Mice in the sham groups were injected with vehicle.The mice were divided into eight groups(n=5):The WT sham 24 h and 4 d groups,the WT colitis 24 h and 4 d groups,the KO sham 24 h and 4 d groups,and the KO colitis 24 h and 4 d groups.The disease activity index(DAI)was analyzed,the distal colon was collected for immunohistochemistry analyses,and immunofluorescence was performed to identify neurons immunoreactive(ir)for calretinin,P2X7 receptor,cleaved caspase-3,total caspase-3,phospho-NF-κB,and total NF-κB.We analyzed the number of calretinin-ir and P2X7 receptor-ir neurons per ganglion,the neuronal profile area(μm^(2)),and corrected total cell fluorescence(CTCF).RESULTS Cells double labeled for calretinin and P2X7 receptor,cleaved caspase-3,total caspase-3,phospho-NF-κB,or total NF-κB were observed in the WT colitis 24 h and 4 d groups.The number of calretinin-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(2.10±0.13 vs 3.33±0.17,P<0.001;2.92±0.12 vs 3.70±0.11,P<0.05),but was not significantly different between the KO groups.The calretinin-ir neuronal profile area was increased in the WT colitis 24 h group compared to the WT sham 24 h group(312.60±7.85 vs 278.41±6.65,P<0.05),and the nuclear profile area was decreased in the WT colitis 4 d group compared to the WT sham 4 d group(104.63±2.49 vs 117.41±1.14,P<0.01).The number of P2X7 receptor-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(19.49±0.35 vs 22.21±0.18,P<0.001;20.35±0.14 vs 22.75±0.51,P<0.001),and no P2X7 receptor-ir neurons were observed in the KO groups.Myenteric neurons showed ultrastructural changes in the WT colitis 24 h and 4 d groups and in the KO colitis 24 h group.The cleaved caspase-3 CTCF was increased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(485949±14140 vs 371371±16426,P<0.001;480381±11336 vs 378365±4053,P<0.001),but was not significantly different between the KO groups.The total caspase-3 CTCF,phospho-NF-κB CTCF,and total NF-κB CTCF were not significantly different among the groups.The DAI was recovered in the KO groups.Furthermore,we demonstrated that the absence of the P2X7 receptor attenuated inflammatory infiltration,tissue damage,collagen deposition,and the decrease in the number of goblet cells in the distal colon.CONCLUSION Ulcerative colitis affects myenteric neurons in WT mice but has a weaker effect in P2X7 receptor KO mice,and neuronal death may be associated with P2X7 receptor-mediated caspase-3 activation.The P2X7 receptor can be a therapeutic target for IBDs.

Functional Insights of Plant GSK3-like Kinases： Multi-Taskers in Diverse Cellular Signal Transduction Pathways

The physiological importance of GSK3-like kinases in plants emerged when the functional role of plant GSK3-like kinases represented by BIN2 was first elucidated in the brassinosteroid （BR）-regulated signal transduction pathway. While early studies focused more on understanding how GSK3-like kinases regulate BR signaling, recent studies have implicated many novel substrates of GSK3-like kinases that are involved in a variety of cellular processes as well as BR signaling. Plant GSK3-like kinases play diverse roles in physiological and developmental processes such as cell growth, root and stomatal cell development, flower development, xylem differentiation, light response, and stress responses. Here, we review the progress made in recent years in understanding the versatile functions of plant GSK3-like kinases. Based on the relationship between GSK3-like kinases and their newly identified substrates, we discuss the physiological and biochemical relevance of various cellular signaling mediated by GSK3-like kinases in plants.

Regulation of artificial supramolecular transmembrane signal transduction by selenium-containing artificial enzyme receptors

Signal transduction across lipid bilayers is of profound importance in biological processes.In biological systems,natural enzymes mediate biochemical effects by binding to substrates and facilitating the conversion of external signals into physiological responses.Sequential transmission of biological signals from one enzyme to the next promotes signal transduction with feedforward and feedback mechanisms.Reconstructing these processes in an artificial system provides potential applications and offers a new way to understand fundamental biological processes in depth.However,the design of artificial signal transduction systems regulated by artificial enzyme receptors in a predictable and intelligent manner remains a challenge.Herein,benefiting from the polarity-regulated characteristics of Se-containing compounds with artificial glutathione peroxidase(GPx)activity,we constructed an artificial transmembrane signaling receptor with a Se-containing GPx-like recognition head group,a membrane-anchoring group,and a pre-enzyme end group.The artificial supramolecular signal transduction system containing such signal transduction receptors extends the range of signaling systems based on enzyme regulation,which provides a new way to study natural signal processes in cells and artificially regulated biological processes.

Research progress on interleukin-33 and its roles in the central nervous system

Interleukin-33 （IL-33）, a newly recognized IL-1 family member, is expressed by various tissues and cells. Since it can combine with chromosomes, IL-33 is regarded as an intracellular transcription repressor. Upon proinflammatory stimulation, it is released as an extracellular cytokine to function as an alarmin to dangerous signals. The IL-33 receptor is a heterodimer complex composed of ST2 and the IL-1 receptor accessory protein, the latter being conserved in other IL-1 family members. The IL-33/ST2 signaling pathway plays critical roles in inflammatory and immune diseases, as well as in central nervous system （CNS） diseases. Recently, there has been an increasing focus on IL-33, particularly on its production and functions in the CNS. The present review mainly focuses on progress in research on IL-33, especially its roles in the CNS.

BES1 Functions as the Co-regulator of D53-like SMXLs to Inhibit BRC1 Expression in Strigolactone-Regulated Shoot Branching in Arabidopsis

Shoot branching,determining plant architecture and crop yield,is critically controlled by strigolactones(SLs).However,how SLs inhibit shoot branching after its perception by the receptor complex remains largely obscure.In this study,using the transcriptomic and genetic analyss as well as biochemical studies,we reveal the key role of BES1 in the SL-regulated shoot branching.Wedemonstrate that BES1 and D53-like SMXLs,the substrates of SL receptor complex D14–MAX2,interact with each other to inhibit BRC1 expression,which specifically triggers the SL-regulated transcriptional network in shoot branching.BES1 directly binds the BRC1 promoter and recruits SMXLs to inhibit BRC1 expression.Interestingly,despite being the shared component by SL and brassinosteroid(BR)signaling,BES1 gains signal specificity through different mechanisms in response to BR and SL signals.

Genome-wide identification of abscisic acid(ABA) receptor pyrabactin resistance 1-like protein(PYL) family members and expression analysis of PYL genes in response to different concentrations of ABA stress in Glycyrrhiza uralensis

As abscisic acid(ABA)receptor,the pyrabactin resistance 1-like(PYR/PYL)protein(named PYL for simplicity)plays an important part to unveil the signal transduction of ABA and its regulatory mechanisms.Glycyrrhiza uralensis,a drought-tolerant medicinal plant,is a good model for the mechanism analysis of ABA response and active compound biosynthesis.However,knowledge about PYL family in G.uralensis remains largely unknown.Here,10 PYLs were identified in G.uralensis genome.Characterization analysis indicated that PYLs in G.uralensis(Gu PYLs)are relatively conserved.Phylogenetic analysis showed that Gu PYL1-3 belongs to subfamily I,Gu PYL4-6 and Gu PYL10 belong to subfamily II and Gu PYL7-9 belongs to subfamily III.In addition,transcriptome data presented various expression levels of Gu PYLs under different exogenous ABA stresses.The expression pattern of Gu PYLs was verified by Quantitative real-time polymerase chain reaction(q RT-PCR).The study proved that Gu PYL4,Gu PYL5,Gu PYL8 and Gu PYL9 genes are significantly up-regulated by ABA stress and the response process is dynamic.This study paves the way for elucidating the regulation mechanism of ABA signal to secondary metabolites and improving the cultivation and quality of G.uralensis using agricultural strategies.

MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages

Primary immune thrombocytopenia(ITP)is an autoimmune hemorrhagic disorder in which macrophages play a critical role.Mammalian sterile-20-like kinase 4(MST4),a member of the germinal-center kinase STE20 family,has been demonstrated to be a regulator of inflammation.Whether MST4 participates in the macrophage-dependent inflammation of ITP remains elusive.The expression and function of MST4 in macrophages of ITP patients and THP-1 cells,and of a macrophage-specific Mst4−/−(Mst4ΔM/ΔM)ITP mouse model were determined.Macrophage phagocytic assays,RNA sequencing(RNA-seq)analysis,immunofluorescence analysis,coimmunoprecipitation(co-IP),mass spectrometry(MS),bioinformatics analysis,and phosphoproteomics analysis were performed to reveal the underlying mechanisms.The expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients,and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone treatment.The expression of the MST4 gene was significantly elevated in THP-1-derived M1 macrophages.Silencing of MST4 decreased the expression of M1 macrophage markers and cytokines,and impaired phagocytosis,which could be increased by overexpression of MST4.In a passive ITP mouse model,macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid,attenuated the expression of M1 cytokines,and promoted the predominance of FcγRIIb in splenic macrophages,which resulted in amelioration of thrombocytopenia.Downregulation of MST4 directly inhibited STAT1 phosphorylation,which is essential for M1 polarization of macrophages.Our study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.

Hydrogen sulfide,nitric oxide,and neurodegenerative disorders

Hydrogen Sulfide(H_(2)S)and Nitric Oxide(NO)have become recognized as important gaseous signaling molecules with enormous pharmacological effects,therapeutic value,and central physiological roles.NO is one of the most important regulators of the pathophysiological condition in central nervous system(CNS).It is critical in the various functioning of the brain;however,beyond certain concentration/level,it is toxic.H_(2)S was regarded as toxic gas with the smell like rotten egg.But,it is now regarded as emerging neuroprotectant and neuromodulator.Recently,the use of donors and inhibitors of these signaling molecules have helped us to identify their accurate and precise biological effects.The most abundant neurotransmitter of CNS(glutamate)is the initiator of the reaction that forms NO,and H_(2)S is highly expressed in brain.These molecules are shedding light on the pathogenesis of various neurological disorders.This review is mainly focused on the importance of H_(2)S and NO for normal functioning of CNS.

Origin of the neuro-sensory system: new and expected insights from sponges

The capacity of all cells to respond to stimuli implies the conduction of information at least over short distances.In multicellular organisms,more complex systems of integration and coordination of activities are necessary.In most animals,the processing of information is performed by a nervous system.Among the most basal taxa,sponges are nerveless so that it is traditionally assumed that the integrated neuro-sensory system originated only once in Eumetazoa,a hypothesis not in agreement with some recent phylogenomic studies.The aim of this review is to show that recent data on sponges might provide clues for understanding the origin of this complex system.First,sponges are able to react to external stimuli,and some of them display spontaneous movement activities.These coordinated behaviors involve nervous system-like mechanisms,such as action potentials and/or neurotransmitters.Second,genomic analyses show that sponges possess genes orthologous to those involved in the patterning or function-ing of the neuro-sensory system in Eumetazoa.Finally,some of these genes are expressed in specific cells(flask cells,choanocytes).Together with ultrastructural data,this gives rise to challenging hypotheses concerning cell types that might play neuro-sensory-like roles in sponges.