Browsing by Subject "CENTRAL-NERVOUS-SYSTEM"

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  • Vanlandewijck, Michael; He, Liqun; Mäe, Maarj A. Andaloussi; Andrae, Johanna; Ando, Koji; Del Gaudio, Francesca; Nahar, Khayrun; Lebouvier, Thibaud; Lavina, Barbara; Gouveia, Leonor; Sun, Ying; Raschperger, Elisabeth; Räsänen, Markus; Zarb, Yvette; Mochizuki, Naoki; Keller, Annika; Lendahl, Urban; Betsholtz, Christer (2018)
    Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.
  • Amorim, Diana; David-Pereira, Ana; Marques, Patricia; Puga, Sonia; Rebelo, Patricia; Costa, Patricio; Pertovaara, Antti; Almeida, Armando; Pinto-Ribeiro, Filipa (2014)
  • Albert, Katrina; Voutilainen, Merja H.; Domanskyi, Andrii; Airavaara, Mikko (2017)
    Gene delivery using adeno-associated virus (AAV) vectors is a widely used method to transduce neurons in the brain, especially due to its safety, efficacy, and long-lasting expression. In addition, by varying AAV serotype, promotor, and titer, it is possible to affect the cell specificity of expression or the expression levels of the protein of interest. Dopamine neurons in the substantia nigra projecting to the striatum, comprising the nigrostriatal pathway, are involved in movement control and degenerate in Parkinson's disease. AAV-based gene targeting to the projection area of these neurons in the striatum has been studied extensively to induce the production of neurotrophic factors for disease-modifying therapies for Parkinson's disease. Much less emphasis has been put on AAV-based gene therapy targeting dopamine neurons in substantia nigra. We will review the literature related to targeting striatum and/or substantia nigra dopamine neurons using AAVs in order to express neuroprotective and neurorestorative molecules, as well as produce animal disease models of Parkinson's disease. We discuss difficulties in targeting substantia nigra dopamine neurons and their vulnerability to stress in general. Therefore, choosing a proper control for experimental work is not trivial. Since the axons along the nigrostriatal tract are the first to degenerate in Parkinson's disease, the location to deliver the therapy must be carefully considered. We also review studies using AAV--synuclein (-syn) to target substantia nigra dopamine neurons to produce an -syn overexpression disease model in rats. Though these studies are able to produce mild dopamine system degeneration in the striatum and substantia nigra and some behavioural effects, there are studies pointing to the toxicity of AAV-carrying green fluorescent protein (GFP), which is often used as a control. Therefore, we discuss the potential difficulties in overexpressing proteins in general in the substantia nigra.
  • Pollari, Marjukka; Pellinen, Teijo; Karjalainen-Lindsberg, Marja-Liisa; Kellokumpu-Lehtinen, Pirkko-Liisa; Leivonen, Suvi-Katri; Leppä, Sirpa (2020)
    Objectives Testicular diffuse large B-cell lymphoma (T-DLBCL) is a rare and aggressive extranodal lymphoma. We have previously shown that high content of tumor-infiltrating lymphocytes (TILs) and PD-1 expressing TILs associate with better survival in T-DLBCL. In this study, we have further characterized distinct TIL subtypes and their proportions in association with patient demographics and survival. Methods We used multiplex immunohistochemistry to characterize TIL phenotypes, including cytotoxic T-cells (CTLs; CD8(+), OX40(+), Granzyme B+, Ki-67(+), LAG-3(+), TIM-3(+), PD-1(+)), CD4(+)T-cells (CD3(+), CD4(+), TIM-3(+), LAG-3(+)), regulatory T-cells (Tregs; CD3(+), CD4(+), FoxP3(+)), and T helper 1 cells (Th1; CD3(+), CD4(+), T-bet(+)) in 79 T-DLBCLs, and correlated the findings with patient demographics and outcome. Results We observed a substantial variation in TIL phenotypes between the patients. The most prominent CD8(+)TILs were Ki-67(+)and TIM-3(+)CTLs, whereas the most prominent CD4(+)TILs were FoxP3(+)Tregs. Despite the overall favorable prognostic impact of high TIL content, we found a subpopulation of T-bet(+)FoxP3(+)Tregs that had a significant adverse impact on survival. Lower content of CTLs with activated or exhausted phenotypes correlated with aggressive clinical features. Conclusions Our results demonstrate significant variation in TIL phenotypes and emphasize the adverse prognostic impact of Tregs in T-DLBCL.
  • Fernandez-Lopez, Blanca; Barreiro-Iglesias, Anton; Celina Rodicio, Maria (2016)
    Lampreys recover locomotion following a spinal cord injury (SCI). Glutamate is necessary to initiate and control locomotion and recent data suggest a crucial role for intraspinal neurons in functional recovery following SCI. We aimed to determine whether, in lampreys, axotomized spinal glutamatergic neurons, which lose glutamate immunoreactivity immediately after SCI, recover it later on and to study the long-term evolution and anatomical recovery of the spinal glutamatergic system after SCI. We used glutamate immunoreactivity to study changes in the glutamatergic system, tract-tracing to label axotomized neurons and TUNEL labelling to study cell death. Transections of the cord were made at the level of the fifth gill. TUNEL experiments indicated that cell death is a minor contributor to the initial loss of glutamate immunoreactivity. At least some of the axotomized neurons lose glutamate immunoreactivity, survive and recover glutamate immunoreactivity 1 week post-lesion (wpl). We observed a progressive increase in the number of glutamatergic neurons/processes until an almost complete anatomical recovery at 10 wpl. Among all the glutamatergic populations, the population of cerebrospinal fluid-contacting cells is the only one that never recovers. Our results indicate that full recovery of the glutamatergic system is not necessary for the restoration of function in lampreys.
  • Garcia-Romero, Noemi; Gonzalez-Tejedo, Carmen; Carrion-Navarro, Josefa; Esteban-Rubio, Susana; Rackov, Gorjana; Rodriguez-Fanjul, Vanessa; Oliver-De La Cruz, Jorge; Prat-Acin, Ricardo; Peris-Celda, Maria; Blesa, David; Ramirez-Jimenez, Laura; Sanchez-Gomez, Pilar; Perona, Rosario; Escobedo-Lucea, Carmen; Belda-Iniesta, Cristobal; Ayuso-Sacido, Angel (2016)
    Human gliomas harbour cancer stem cells (CSCs) that evolve along the course of the disease, forming highly heterogeneous subpopulations within the tumour mass. These cells possess self-renewal properties and appear to contribute to tumour initiation, metastasis and resistance to therapy. CSC cultures isolated from surgical samples are considered the best preclinical in vitro model for primary human gliomas. However, it is not yet well characterized to which extent their biological and functional properties change during in vitro passaging in the serum-free culture conditions. Here, we demonstrate that our CSC-enriched cultures harboured from one to several CSC clones from the human glioma sample. When xenotransplanted into mouse brain, these cells generated tumours that reproduced at least three different dissemination patterns found in original tumours. Along the passages in culture, CSCs displayed increased expression of stem cell markers, different ratios of chromosomal instability events, and a varied response to drug treatment. Our findings highlight the need for better characterization of CSC-enriched cultures in the context of their evolution in vitro, in order to uncover their full potential as preclinical models in the studies aimed at identifying molecular biomarkers and developing new therapeutic approaches of human gliomas.
  • Kulesskaya, Natalia; Voikar, Vootele; Peltola, Marjaana; Yegutkin, Gennady G.; Salmi, Marko; Jalkanen, Sirpa; Rauvala, Heikki (2013)
  • Guirado, Ramon; Perez-Rando, Marta; Sanchez-Matarredona, David; Castren, Eero; Nacher, Juan (2014)
  • Martelius, Timi; Lappalainen, Maija; Palomaki, Maarit; Anttila, Veli-Jukka (2011)
  • Jokinen, Viljami; Sidorova, Yulia; Viisanen, Hanna; Suleymanova, Ilida; Tiilikainen, Henna; Li, Zhilin; Lilius, Tuomas O.; Matlik, Kert; Anttila, Jenni E.; Airavaara, Mikko; Tian, Li; Rauhala, Pekka V.; Kalso, Eija A. (2018)
    Development of tolerance is a well known pharmacological characteristic of opioids and a major clinical problem. In addition to the known neuronal mechanisms of opioid tolerance, activation of glia has emerged as a potentially significant new mechanism. We studied activation of microglia and astrocytes in morphine tolerance and opioid-induced hyperalgesia in rats using immunohistochemistry, flow cytometry and RNA sequencing in spinal-and supraspinal regions. Chronic morphine treatment that induced tolerance and hyperalgesia also increased immunoreactivity of spinal microglia in the dorsal and ventral horns. Flow cytometry demonstrated that morphine treatment increased the proportion of M2-polarized spinal microglia, but failed to impact the number or the proportion of M1-polarized microglia. In the transcriptome of microglial cells isolated from the spinal cord (SC), morphine treatment increased transcripts related to cell activation and defense response. In the studied brain regions, no activation of microglia or astrocytes was detected by immunohistochemistry, except for a decrease in the number of microglial cells in the substantia nigra. In flow cytometry, morphine caused a decrease in the number of microglial cells in the medulla, but otherwise no change was detected for the count or the proportion of M1-and M2-polarized microglia in the medulla or sensory cortex. No evidence for the activation of glia in the brain was seen. Our results suggest that glial activation associated with opioid tolerance and opioid-induced hyperalgesia occurs mainly at the spinal level. The transcriptome data suggest that the microglial activation pattern after chronic morphine treatment has similarities with that of neuropathic pain. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Patel, Tirth K.; Habimana-Griffin, LeMoyne; Gao, Xuefeng; Xu, Baogang; Achilefu, Samuel; Alitalo, Kari; McKee, Celia A.; Sheehan, Patrick W.; Musiek, Erik S.; Xiong, Chengjie; Coble, Dean; Holtzman, David M. (2019)
    BackgroundAlzheimer's disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid- (A) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), some forms of frontotemporal dementia, and argyrophilic grain disease (AGD). The prion hypothesis suggests that after an initial trigger event, misfolded forms of tau are released into the extracellular space, where they spread through different brain regions, enter cells, and seeding previously normal forms. Thus understanding mechanisms regulating the clearance of extracellular tau from the CNS is important. The discovery of a true lymphatic system in the dura and its potential role in mediating A pathology prompted us to investigate its role in regulating extracellular tau clearance.MethodsTo study clearance of extracellular tau from the brain, we conjugated monomeric human tau with a near-infrared dye cypate, and injected this labeled tau in the parenchyma of both wild-type and K14-VEGFR3-Ig transgenic mice, which lack a functional CNS lymphatic system. Following injection we performed longitudinal imaging using fluorescence molecular tomography (FMT) and quantified fluorescence to calculate clearance of tau from the brain. To complement this, we also measured tau clearance to the periphery by measuring plasma tau in both groups of mice.ResultsOur results show that a significantly higher amount of tau is retained in the brains of K14-VEGFR3-Ig vs. wild type mice at 48 and 72h post-injection and its subsequent clearance to the periphery is delayed. We found that clearance of reference tracer human serum albumin (HSA) was also significantly delayed in the K14-VEGFR3-Ig mice.ConclusionsThe dural lymphatic system appears to play an important role in clearance of extracellular tau, since tau clearance is impaired in the absence of functional lymphatics. Based on our baseline characterization of extracellular tau clearance, future studies are warranted to look at the interaction between tau pathology and efficiency of lymphatic function.
  • Hautala, Timo; Partanen, Terhi; Sironen, Tarja; Rajaniemi, Saara-Mari; Hautala, Nina; Vainio, Olli; Vapalahti, Olli; Kauma, Heikki; Vaheri, Antti (2013)
  • Hikmat, Omar; Naess, Karin; Engvall, Martin; Klingenberg, Claus; Rasmussen, Magnhild; Tallaksen, Chantal M. E.; Brodtkorb, Eylert; Fiskerstrand, Torunn; Isohanni, Pirjo; Uusimaa, Johanna; Darin, Niklas; Rahman, Shamima; Bindoff, Laurence A. (2018)
    Objective: Epilepsy is common in individuals with mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma. Early recognition and aggressive seizure management are crucial for patient survival. Disruption of the blood-brain barrier (BBB) is implicated in various neurological disorders including epilepsy. The aim of this study was to assess whether POLG-related disease is associated with BBB dysfunction and what clinical implications this has for patients. Methods: Our retrospective study used data from 83 patients with pathogenic POLG mutations from 4 countries-Norway, Sweden, Finland, and the United Kingdom. Data were collected using a structured questionnaire. We used the presence of raised cerebrospinal fluid (CSF) protein and a raised CSF/serum ratio of albumin (Q-alb) to evaluate the integrity of the blood-CSF bather. Results: Raised CSF protein was found in 70% of patients (n = 58/83) and appeared to be associated with the most severe phenotypes. In those in whom it was measured, the Q-alb ratio was markedly elevated (n = 18). The majority of those with epilepsy (n = 50/66, 76%) had raised CSF protein, and this preceded seizure debut in 75% (n = 15/20). The median survival time from symptom onset for those with raised CSF protein was decreased (13 months) compared to those with normal CSF protein (32 months). Significance: Our results indicate that there is disruption of the BBB in POLG-related disease, as evidenced by a raised CSF protein and Q-alb ratio. We also find that raised CSF protein is a common finding in patients with POLG disease. Our data suggest that the presence of BBB dysfunction predicts a poorer outcome, and elevated CSF protein may therefore be an additional biomarker both for early diagnosis and to identify those at high risk of developing epilepsy.
  • Turunen, Pauli M.; Louhivuori, Lauri M.; Louhivuori, Verna; Kukkonen, Jyrki P.; Akerman, Karl E. (2018)
    Cell-cell communication plays a central role in the guidance of migrating neuronal precursor cells during the development of the cerebral cortex. Endocannabinoids (eCBs) have previously been shown to be one of the central factors regulating neuronal migration. In this study the effects of eCBs on different parameters, expected to affect embryonic cortical neuronal motility have been analyzed in neurosphere-derived neuroblasts using time-lapse microscopy. Increased endogenous production of the endocannabinoid 2-arachidonyl glycerol (2-AG) causes bursts of neuroblast motility. The neuroblasts move longer distances and show a low frequency of turning, and the number of neuron-neuron contacts are reduced. Similar changes occur interfering with the function of the metabotropic glutamate receptor 5 (mGluR5) or its transducer canonical transient receptor potential channel 3 (TRPC3) or the neuregulin receptor ErbB4. Blocking of 2-AG production reverses these effects. The data suggest that eCB-regulated neuronal motility is controlled by mGluR5/TRPC3 activity possibly via NRG/ErbB4 signaling. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Lido, Helga Hoifodt; Jonsson, Susanne; Hyytiä, Petri; Ericson, Mia; Soderpalm, Bo (2017)
    The glycine transporter-1 inhibitor Org25935 is a promising candidate in a treatment concept for alcohol use disorder targeting the glycine system. Org25935 inhibits ethanol-induced dopamine elevation in brain reward regions and reduces ethanol intake in Wistar rats. This study aimed to further characterise the compound and used ethanol consumption, behavioral measures, and gene expression as parameters to investigate the effects in Wistar rats and, as pharmacogenetic comparison, Alko-Alcohol (AA) rats. Animals were provided limited access to ethanol in a two-bottle free-choice paradigm with daily drug administration. Acute effects of Org25935 were estimated using locomotor activity and neurobehavioral status. Effects on gene expression in Wistar rats were measured with qPCR. The higher but not the lower dose of Org25935 reduced alcohol intake in Wistar rats. Unexpectedly, Org25935 reduced both ethanol and water intake and induced strong CNS-depressive effects in AA-rats (withdrawn from further studies). Neurobehavioral effects by Org25935 differed between the strains (AA-rats towards sedation). Org25935 did not affect gene expression at the mRNA level in the glycine system of Wistar rats. The data indicate a small therapeutic range for the anti-alcohol properties of Org25935, a finding that may guide further evaluations of the clinical utility of GlyT-1 inhibitors. The results point to the importance of pharmacogenetic considerations when developing drugs for alcohol-related medical concerns. Despite the lack of successful clinical outcomes, to date, the heterogeneity of drug action of Org25935 and similar agents and the unmet medical need justify further studies of glycinergic compounds in alcohol use disorder.
  • Korber, Inken; Katayama, Shintaro; Einarsdottir, Elisabet; Krjutskov, Kaarel; Hakala, Paula; Kere, Juha; Lehesjoki, Anna-Elina; Joensuu, Tarja (2016)
    Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1, OMIM254800) is an autosomal recessive neurodegenerative disorder characterized by stimulus-sensitive and action-activated myoclonus, tonic-clonic epileptic seizures, and ataxia. Loss-of-function mutations in the gene encoding the cysteine protease inhibitor cystatin B (CSTB) underlie EPM1. The deficiency of CSTB in mice (Cstb(-/-) mice) generates a phenotype resembling the symptoms of EPM1 patients and is accompanied by microglial activation at two weeks of age and an upregulation of immune system-associated genes in the cerebellum at one month of age. To shed light on molecular pathways and processes linked to CSTB deficiency in microglia we characterized the transcriptome of cultured Cstb(-/-) mouse microglia using microarray hybridization and RNA sequencing (RNA-seq). The gene expression profiles obtained with these two techniques were in good accordance and not polarized to either pro- or anti-inflammatory status. In Cstb(-/-) microglia, altogether 184 genes were differentially expressed. Of these, 33 genes were identified by both methods. Several interferon-regulated genes were weaker expressed in Cstb(-/-) microglia compared to control. This was confirmed by quantitative real-time PCR of the transcripts Irf7 and Stat1. Subsequently, we explored the biological context of CSTB deficiency in microglia more deeply by functional enrichment and canonical pathway analysis. This uncovered a potential role for CSTB in chemotaxis, antigen-presentation, and in immune-and defense response-associated processes by altering JAK-STAT pathway signaling. These data support and expand the previously suggested involvement of inflammatory processes to the disease pathogenesis of EPM1 and connect CSTB deficiency in microglia to altered expression of interferon-regulated genes.
  • Laine, Mikaela A.; Trontti, Kalevi; Misiewicz, Zuzanna; Sokolowska, Ewa; Kulesskaya, Natalia; Heikkinen, Aino; Saarnio, Suvi; Balcells, Ingrid; Ameslon, Pierre; Greco, Dario; Mattila, Pirkko; Ellonen, Pekka; Paulin, Lars; Auvinen, Petri; Jokitalo, Eija; Hovatta, Iiris (2018)
    Anxiety disorders often manifest in genetically susceptible individuals after psychosocial stress, but the mechanisms underlying these gene-environment interactions are largely unknown. We used the chronic social defeat stress (CSDS) mouse model to study resilience and susceptibility to chronic psychosocial stress. We identified a strong genetic background effect in CSDS-induced social avoidance (SA) using four inbred mouse strains: 69% of C57BL/6NCrl (B6), 23% of BALB/cAnNCrl, 19% of 129S2/SvPasCrl, and 5% of DBA/2NCrl (D2) mice were stress resilient. Furthermore, different inbred mouse strains responded differently to stress, suggesting they use distinct coping strategies. To identify biological pathways affected by CSDS, we used RNA-sequencing (RNAseq) of three brain regions of two strains, B6 and D2: medial prefrontal cortex (mPFC), ventral hippocampus (vHPC), and bed nucleus of the stria terminalis (BNST). We discovered overrepresentation of oligodendrocyte (OLG)-related genes in the differentially expressed gene population. Because OLGs myelinate axons, we measured myelin thickness and found significant region and strain-specific differences. For example, in resilient D2 mice, mPFC axons had thinner myelin than controls, whereas susceptible B6 mice had thinner myelin than controls in the vHPC. Neither myelin-related gene expression in several other regions nor corpus callosum thickness differed between stressed and control animals. Our unbiased gene expression experiment suggests that myelin plasticity is a substantial response to chronic psychosocial stress, varies across brain regions, and is genetically controlled. Identification of genetic regulators of the myelin response will provide mechanistic insight into the molecular basis of stress-related diseases, such as anxiety disorders, a critical step in developing targeted therapy.
  • Korja, Miikka; Raj, Rahul; Seppä, Karri; Luostarinen, Tapio; Malila, Nea; Seppälä, Matti; Mäenpää, Hanna; Pitkäniemi, Janne (2019)
    We assessed population-level changes in glioblastoma survival between 2000 and 2013 in Finland, with focus on elderly patients (> 70 y) in order to assess if changes in treatment of glioblastoma are reflected also in population-based survival rates. We identified all patients (age 18 y) from the Finnish Cancer Registry (FCR) with a histopathological diagnosis of primary glioblastoma in 20002013. Patients were followed up until December 2015. The accuracy of register-based search of glioblastoma patients was internally validated. We report age-standardized relative survival ratios and relative excess risks (RERs) of death in 20002006 (pre-period) and 20072013 (post-period). We identified 2045 glioblastoma patients from the FCR. The accuracy of the FCR-based search was 97%. Median age was 63.3 years, and 42% were women. Incidence increased on average by 1.6% (P = 0.004) and median age by 0.4 years per calendar year. Between the pre- and post-periods, the proportion of patients > 70 years increased from 24% to 27%. In > 70-year-old patients, the median survival time increased from 3.6 months in 20002006 to 4.5 months in 20072013 (RER 0.82, 95% CI: 0.680.98). In 70-year-old patients, the median survival time increased from 9.3 months in 20002006 to 11.7 months in 20072013 (RER 0.74, 95% CI: 0.670.82). Despite the increased proportion of elderly glioblastoma patients, population-level survival of glioblastoma patients has improved since the year 2000. However, increasing incidence, increasing age of patients, and poor survival in elderly are alarming, and future studies should perhaps focus more on elderly.
  • Paveliev, Mikhail; Fenrich, Keith K.; Kislin, Mikhail; Kuja-Panula, Juha; Kulesskiy, Evgeny; Varjosalo, Markku; Kajander, Tommi; Mugantseva, Ekaterina; Ahonen-Bishopp, Anni; Khirug, Leonard; Kulesskaya, Natalia; Rougon, Genevieve; Rauvala, Heikki (2016)
    Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPs (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries.
  • Salvador-Martinez, Irepan; Salazar-Ciudad, Isaac (2017)
    The increase in complexity in an embryo over developmental time is perhaps one of the most intuitive processes of animal development. It is also intuitive that the embryo becomes progressively compartmentalized over time and space. In spite of this intuitiveness, there are no systematic attempts to quantify how this occurs. Here, we present a quantitative analysis of the compartmentalization and spatial complexity of Ciona intestinalis over developmental time by analyzing thousands of gene expression spatial patterns from the ANISEED database. We measure compartmentalization in two ways: as the relative volume of expression of genes and as the disparity in gene expression between body parts. We also use a measure of the curvature of each gene expression pattern in 3D space. These measures show a similar increase over time, with the most dramatic change occurring from the 112-cell stage to the early tailbud stage. Combined, these measures point to a global pattern of increase in complexity in the Ciona embryo. Finally, we cluster the different regions of the embryo depending on their gene expression similarity, within and between stages. Results from this clustering analysis, which partially correspond to known fate maps, provide a global quantitative overview about differentiation and compartmentalization between body parts at each developmental stage. (C) 2017 Elsevier B.V. All rights reserved.