Browsing by Subject "NEUROGENESIS"

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  • Jacob, Laurent; Boisserand, Ligia Simoes Braga; Geraldo, Luiz Henrique Medeiros; Neto, Jose de Brito; Mathivet, Thomas; Antila, Salli; Barka, Besma; Xu, Yunling; Thomas, Jean-Mickael; Pestel, Juliette; Aigrot, Marie-Stephane; Song, Eric; Nurmi, Harri; Lee, Seyoung; Alitalo, Kari; Renier, Nicolas; Eichmann, Anne; Thomas, Jean-Leon (2019)
    Cranial lymphatic vessels (LVs) are involved in the transport of fluids, macromolecules and central nervous system (CNS) immune responses. Little information about spinal LVs is available, because these delicate structures are embedded within vertebral tissues and difficult to visualize using traditional histology. Here we show an extended vertebral column LV network using three-dimensional imaging of decalcified iDISCO(+)-clarified spine segments. Vertebral LVs connect to peripheral sensory and sympathetic ganglia and form metameric vertebral circuits connecting to lymph nodes and the thoracic duct. They drain the epidural space and the dura mater around the spinal cord and associate with leukocytes. Vertebral LVs remodel extensively after spinal cord injury and VEGF-C-induced vertebral lymphangiogenesis exacerbates the inflammatory responses, T cell infiltration and demyelination following focal spinal cord lesion. Therefore, vertebral LVs add to skull meningeal LVs as gatekeepers of CNS immunity and may be potential targets to improve the maintenance and repair of spinal tissues.
  • Peltopuro, Paula; Kala, Kaia; Partanen, Juha (2010)
  • Balasubramanian, Vimalkumar; Domanskyi, Andrii; Renko, Juho-Matti; Sarparanta, Mirkka; Wang, Chang-Fang; Rebelo Correia, Alexandra Maria; Mäkilä, Ermei; Alanen, Osku; Salonen, Jarno; Airaksinen, Anu; Tuominen, Raimo K.; Hirvonen, Jouni; Airavaara, Mikko; Santos, Hélder A. (2020)
    Generation of new neurons by utilizing the regenerative potential of adult neural stem cells (NSCs) and neuroblasts is an emerging therapeutic strategy to treat various neurodegenerative diseases, including neuronal loss after stroke. Committed to neuronal lineages, neuroblasts are differentiated from NSCs and have a lower proliferation rate. In stroke the proliferation of the neuroblasts in the neurogenic areas is increased, but the limiting factor for regeneration is the poor survival of migrating neuroblasts. Survival of neuroblasts can be promoted by small molecules; however, new drug delivery methods are needed to specifically target these cells. Herein, to achieve specific targeting, we have engineered biofunctionalized porous silicon nanoparticles (PSi NPs) conjugated with a specific antibody against polysialylated neural cell adhesion molecule (PSA-NCAM). The PSi NPs loaded with a small molecule drug, SC-79, were able to increase the activity of the Akt signaling pathway in doublecortin positive neuroblasts both in cultured cells and in vivo in the rat brain. This study opens up new possibilities to target drug effects to migrating neuroblasts and facilitate differentiation, maturation and survival of developing neurons. The conjugated PSi NPs are a novel tool for future studies to develop new therapeutic strategies aiming at regenerating functional neurocircuitry after stoke.
  • Herczeg, Gabor; Gonda, Maria Abigel; Balazs, Gergely; Noreikiene, Kristina; Merila, Juha (2015)
    Background: Plasticity in brain size and the size of different brain regions during early ontogeny is known from many vertebrate taxa, but less is known about plasticity in the brains of adults. In contrast to mammals and birds, most parts of a fish's brain continue to undergo neurogenesis throughout adulthood, making lifelong plasticity in brain size possible. We tested whether maturing adult three-spined sticklebacks (Gasterosteus aculeatus) reared in a stimulus-poor environment exhibited brain plasticity in response to environmental enrichment, and whether these responses were sex-specific, thus altering the degree of sexual size dimorphism in the brain. Results: Relative sizes of total brain and bulbus olfactorius showed sex-specific responses to treatment: males developed larger brains but smaller bulbi olfactorii than females in the enriched treatment. Hence, the degree of sexual size dimorphism (SSD) in relative brain size and the relative size of the bulbus olfactorius was found to be environment-dependent. Furthermore, the enriched treatment induced development of smaller tecta optica in both sexes. Conclusions: These results demonstrate that adult fish can alter the size of their brain (or brain regions) in response to environmental stimuli, and these responses can be sex-specific. Hence, the degree of SSD in brain size can be environment-dependent, and our results hint at the possibility of a large plastic component to SSD in stickleback brains. Apart from contributing to our understanding of the processes shaping and explaining variation in brain size and the size of different brain regions in the wild, the results show that provision of structural complexity in captive environments can influence brain development. Assuming that the observed plasticity influences fish behaviour, these findings may also have relevance for fish stocking, both for economical and conservational purposes.
  • Steinzeig, Anna; Cannarozzo, Cecilia; Castren, Eero (2019)
    Heightened neuronal plasticity expressed during early postnatal life has been thought to permanently decline once critical periods have ended. For example, monocular deprivation is able to shift ocular dominance in the mouse visual cortex during the first months of life, but this effect is lost later in life. However, various treatments, such as the antidepressant fluoxetine, can reactivate a critical period-like plasticity in the adult brain. When monocular deprivation is supplemented with chronic fluoxetine administration, a major shift in ocular dominance is produced after the critical period has ended. In the current study, we characterized the temporal patterns of fluoxetine-induced plasticity in the adult mouse visual cortex, using in vivo optical imaging. We found that artificially induced plasticity in ocular dominance extended beyond the duration of the naturally occurring critical period and continued as long as fluoxetine was administered. However, this fluoxetine-induced plasticity period ended as soon as the drug was not given. These features of antidepressant-induced plasticity may be useful when designing treatment strategies involving long-term antidepressant treatment in humans.
  • Schormair, Barbara; Zhao, Chen; Bell, Steven; Tilch, Erik; Salminen, Aaro V.; Puetz, Benno; Dauvilliers, Yves; Stefani, Ambra; Hoegl, Birgit; Poewe, Werner; Kemlink, David; Sonka, Karel; Bachmann, Cornelius G.; Paulus, Walter; Trenkwalder, Claudia; Oertel, Wolfgang H.; Hornyak, Magdolna; Teder-Laving, Maris; Metspalu, Andres; Hadjigeorgiou, Georgios M.; Polo, Olli; Fietze, Ingo; Ross, Owen A.; Wszolek, Zbigniew; Butterworth, Adam S.; Soranzo, Nicole; Ouwehand, Willem H.; Roberts, David J.; Danesh, John; Allen, Richard P.; Earley, Christopher J.; Ondo, William G.; Xiong, Lan; Montplaisir, Jacques; Gan-Or, Ziv; Perola, Markus; Vodicka, Pavel; Dina, Christian; Franke, Andre; Tittmann, Lukas; Stewart, Alexandre F. R.; Shah, Svati H.; Gieger, Christian; Peters, Annette; Rouleau, Guy A.; Berger, Klaus; Oexle, Konrad; Di Angelantonio, Emanuele; Hinds, David A.; Mueller-Myhsok, Bertram; Collaboration 23andMe Res Team; DESIR Study Grp (2017)
    Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1.92, 95% CI 1 85-1.99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations.
  • Utami, Kagistia Hana; Skotte, Nils H.; Colaco, Ana R.; Yusof, Nur Amirah Binte Mohammad; Sim, Bernice; Yeo, Xin Yi; Bae, Han-Gye; Garcia-Miralles, Marta; Radulescu, Carola I.; Chen, Qiyu; Chaldaiopoulou, Georgia; Liany, Herty; Nama, Srikanth; Peteri, Ulla-Kaisa A.; Sampath, Prabha; Castrén, Maija; Jung, Sangyong; Mann, Matthias; Pouladi, Mahmoud (2020)
    BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have been largely performed in rodent or nonisogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal properties in the context of isogenic human neurons remains lacking. METHODS: Using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to introduce indels in exon 3 of FMR1, we generated an isogenic human pluripotent stem cell model of FXS that shows complete loss of FMRP expression. We generated neuronal cultures and performed genome-wide transcriptome and proteome profiling followed by functional validation of key dysregulated processes. We further analyzed neurodevelopmental and neuronal properties, including neurite length and neuronal activity, using multielectrode arrays and patch clamp electrophysiology. RESULTS: We showed that the transcriptome and proteome profiles of isogenic FMRP-deficient neurons demonstrate perturbations in synaptic transmission, neuron differentiation, cell proliferation and ion transmembrane transporter activity pathways, and autism spectrum disorder-associated gene sets. We uncovered key deficits in FMRP-deficient cells demonstrating abnormal neural rosette formation and neural progenitor cell proliferation. We further showed that FMRP-deficient neurons exhibit a number of additional phenotypic abnormalities, including neurite outgrowth and branching deficits and impaired electrophysiological network activity. These FMRP-deficient related impairments have also been validated in additional FXS patient-derived human-induced pluripotent stem cell neural cells. CONCLUSIONS: Using isogenic human pluripotent stem cells as a model to investigate the pathophysiology of FXS in human neurons, we reveal key neural abnormalities arising from the loss of FMRP.
  • Yu, Seong-Jin; Tseng, Kuan-Yin; Shen, Hui; Harvey, Brandon K.; Airavaara, Mikko; Wang, Yun (2013)
  • De Gregorio, Roberto; Pulcrano, Salvatore; De Sanctis, Claudia; Volpicelli, Floriana; Guatteo, Ezia; von Oerthel, Lars; Latagliata, Emanuele Claudio; Esposito, Roberta; Piscitelli, Rosa Maria; Perrone-Capano, Carla; Costa, Valerio; Greco, Dario; Puglisi-Allegra, Stefano; Smidt, Marten P.; di Porzio, Umberto; Caiazzo, Massimiliano; Mercuri, Nicola Biagio; Li, Meng; Bellenchi, Gian Carlo (2018)
    The differentiation of dopaminergic neurons requires concerted action of morphogens and transcription factors acting in a precise and well-defined time window. Very little is known about the potential role of microRNA in these events. By performing a microRNA-mRNA paired microarray screening, we identified miR-34b/c among the most upregulated microRNAs during dopaminergic differentiation. Interestingly, miR-34b/c modulates Wnt1 expression, promotes cell cycle exit, and induces dopaminergic differentiation. When combined with transcription factors ASCL1 and NURR1, miR-34b/c doubled the yield of transdifferentiated fibroblasts into dopaminergic neurons. Induced dopaminergic (iDA) cells synthesize dopamine and show spontaneous electrical activity, reversibly blocked by tetrodotoxin, consistent with the electrophysiological properties featured by brain dopaminergic neurons. Our findings point to a role for miR-34b/c in neuronal commitment and highlight the potential of exploiting its synergy with key transcription factors in enhancing in vitro generation of dopaminergic neurons.
  • Gabriel, Elke; Ramani, Anand; Karow, Ulrike; Gottardo, Marco; Natarajan, Karthick; Gooi, Li Ming; Goranci-Buzhala, Gladiola; Krut, Oleg; Peters, Franziska; Nikolic, Milos; Kuivanen, Suvi; Hasu, Essi; Smura, Teemu; Vapalahti, Olli; Papantonis, Argyris; Schmidt-Chanasit, Jonas; Riparbelli, Maria; Callaini, Giuliano; Kroenke, Martin; Utermoehlen, Olaf; Gopalakrishnan, Jay (2017)
    The recent Zika virus (ZIKV) epidemic is associated with microcephaly in newborns. Although the connection between ZIKV and neurodevelopmental defects is widely recognized, the underlying mechanisms are poorly understood. Here we show that two recently isolated strains of ZIKV, an American strain from an infected fetal brain (FB-GWUH-2016) and a closely-related Asian strain (H/PF/2013), productively infect human iPSC-derived brain organoids. Both of these strains readily target to and replicate in proliferating ventricular zone (VZ) apical progenitors. The main phenotypic effect was premature differentiation of neural progenitors associated with centrosome perturbation, even during early stages of infection, leading to progenitor depletion, disruption of the VZ, impaired neurogenesis, and cortical thinning. The infection pattern and cellular outcome differ from those seen with the extensively passaged ZIKV strain MR766. The structural changes we see after infection with these more recently isolated viral strains closely resemble those seen in ZIKV-associated microcephaly.
  • Nordström, Tommy; Andersson, Leif C.; Åkerman, Karl E. O. (2019)
    A stroke causes a hypoxic brain microenvironment that alters neural cell metabolism resulting in cell membrane hyperpolarization and intracellular acidosis. We studied how intracellular pH (pH(i)) is regulated in differentiated mouse neural progenitor cells during hyperpolarizing conditions, induced by prompt reduction of the extra cellular K+ concentration. We found that the radial glia-like population in differentiating embryonic neural progenitor cells, but not neuronal cells, was rapidly acidified under these conditions. However, when extra cellular calcium was removed, an instant depolarization and recovery of the pH(i), back to normal levels, took place. The rapid recovery phase seen in the absence of calcium, was dependent on extracellular bicarbonate and could be inhibited by 50859, a potent Na/HCO3 cotransporter inhibitor. Immunostaining and PCR data, showed that NBCe1 (SLC4A4) and NBCn1 (SLC4A7) were expressed in the cell population and that the pH(i) recovery in the radial glial-like cells after calcium removal was mediated mainly by the electrogenic sodium bicarbonate transporter NBCe1 (SLC4A4). Our results indicate that extracellular calcium might hamper pH(i) regulation and Na/HCO3 cotransporter activity in a brain injury microenvironment. Our findings show that the NBC-type transporters are the main pH(i) regulating systems prevailing in glia-like progenitor cells and that these calcium sensitive transporters are important for neuronal progenitor cell proliferation, survival and neural stem cell differentiation.
  • Tegelberg, Saara; Tomasic, Nikica; Kallijärvi, Jukka; Purhonen, Janne; Elmer, Eskil; Lindberg, Eva; Nord, David Gisselsson; Soller, Maria; Lesko, Nicole; Wedell, Anna; Bruhn, Helene; Freyer, Christoph; Stranneheim, Henrik; Wibom, Rolf; Nennesmo, Inger; Wredenberg, Anna; Eklund, Erik A.; Fellman, Vineta (2017)
    Background: Mitochondrial diseases due to defective respiratory chain complex III (CIII) are relatively uncommon. The assembly of the eleven-subunit CIII is completed by the insertion of the Rieske iron-sulfur protein, a process for which BCS1L protein is indispensable. Mutations in the BCS1L gene constitute the most common diagnosed cause of CIII deficiency, and the phenotypic spectrum arising from mutations in this gene is wide. Results: A case of CIII deficiency was investigated in depth to assess respiratory chain function and assembly, and brain, skeletal muscle and liver histology. Exome sequencing was performed to search for the causative mutation(s). The patient's platelets and muscle mitochondria showed respiration defects and defective assembly of CIII was detected in fibroblast mitochondria. The patient was compound heterozygous for two novel mutations in BCS1L, c.306A > T and c.399delA. In the cerebral cortex a specific pattern of astrogliosis and widespread loss of microglia was observed. Further analysis showed loss of Kupffer cells in the liver. These changes were not found in infants suffering from GRACILE syndrome, the most severe BCS1L-related disorder causing early postnatal mortality, but were partially corroborated in a knock-in mouse model of BCS1L deficiency. Conclusions: We describe two novel compound heterozygous mutations in BCS1L causing CIII deficiency. The pathogenicity of one of the mutations was unexpected and points to the importance of combining next generation sequencing with a biochemical approach when investigating these patients. We further show novel manifestations in brain, skeletal muscle and liver, including abnormality in specialized resident macrophages (microglia and Kupffer cells). These novel phenotypes forward our understanding of CIII deficiencies caused by BCS1L mutations.
  • de Groot, Claire; Floriou-Servou, Amalia; Tsai, Yuan-Chen; Fruh, Simon; Kohler, Manuela; Parkin, Georgia; Schwerdel, Cornelia; Bosshard, Giovanna; Kaila, Kai; Fritschy, Jean-Marc; Tyagarajan, Shiva K. (2017)
    In developing brain neuronal migration, dendrite outgrowth and dendritic spine outgrowth are controlled by Cdc42, a small GTPase of the Rho family, and its activators. Cdc42 function in promoting actin polymerization is crucial for glutamatergic synapse regulation. Here, we focus on GABAergic synapse-specific activator of Cdc42, collybistin ( CB) and examine functional differences between its splice isoforms CB1 and CB2. We report that CB1 and CB2 differentially regulate GABAergic synapse formation in vitro along proximal-distal axis and adult-born neuron maturation in vivo. The functional specialization between CB1 and CB2 isoforms arises from their differential protein half-life, in turn regulated by ubiquitin conjugation of the unique CB1 C-terminus. We report that CB1 and CB2 negatively regulate Cdc42; however, Cdc42 activation is dependent on CB interaction with gephyrin. During hippocampal adult neurogenesis CB1 regulates neuronal migration, while CB2 is essential for dendrite outgrowth. Finally, using mice lacking Gabra2 subunit, we show that CB1 function is downstream of GABA(A)Rs, and we can rescue adult neurogenesis deficit observed in Gabra2 KO. Overall, our results uncover previously unexpected role for CB isoforms downstream of alpha 2-containing GABA(A)Rs during neuron maturation in a Cdc42 dependent mechanism.
  • Buechel, Severine D.; Noreikiene, Kristina; DeFaveri, Jacquelin; Toli, Elisavet; Kolm, Niclas; Merila, Juha (2019)
    Snapshot analyses have demonstrated dramatic intraspecific variation in the degree of brain sexual size dimorphism (SSD). Although brain SSDis believed to be generated by the sex-specific cognitive demands of reproduction, the relative roles of developmental and population-specific contributions to variation in brain SSD remain little studied. Using a common garden experiment, we tested for sex-specific changes in brain anatomy over the breeding cycle in three-spined stickleback (Gasterosteus aculeatus) sampled from four locations in northern Europe. We found that the male brain increased in size (ca. 24%) significantly more than the female brain towards breeding, and that the resulting brain SSD was similar (ca. 20%) for all populations over the breeding cycle. Our findings support the notion that the stickleback brain is highly plastic and changes over the breeding cycle, especially in males, likely as an adaptive response to the cognitive demands of reproduction (e.g. nest construction and parental care). The results also provide evidence to suggest that breeding-related changes in brain size may be the reason for the widely varying estimates of brain SSD across studies of this species, cautioning against interpreting brain size measurements from a single time point as fixed/static.
  • Eymann, Julia; Salomies, Lotta; Macrì, Simone; Di-Poï, Nicolas (2019)
    Abstract The retina is a complex, multilayered tissue responsible for the perception of visual stimuli from the environment. Contrary to mammals, the capacity for postnatal eye growth in fish and amphibians, and to a lower extent in birds, is coordinated with a progenitor population residing in the ciliary marginal zone (CMZ) at the retinal peripheral margin. However, little is known about embryonic retinogenesis and postnatal retinal growth in squamates (lizards, snakes), despite their exceptional array of ecologies and ocular morphologies. Here we address this gap by performing the first large-scale study assessing both ontogenetic and adult changes in the stem/progenitor activity of the squamate peripheral retina. Our study reveals for the first time that squamates exhibit a source of proliferating progenitors persisting post embryogenesis in a newly identified retinociliary junction anteriorly adjacent to the retina. This region is strikingly similar to the vertebrate CMZ by its peripheral location and pseudostratified nature, and shares a common pattern of slow-cycling cells, spatial differentiation gradient, and response to postnatal ocular growth. Additionally, its proliferative activity varies considerably among squamate species, in correlation with embryonic and postnatal differences in eye size and growth. Together our data indicate that squamates possess a proliferative peripheral retina that acts as a source of progenitors to compensate, at least in part, for postnatal ocular growth. Our findings also highlight the remarkable variation in activity and location of vertebrate retinal progenitors, indicating that the currently accepted scenario of reduced CMZ activity over the course of evolution is too simplistic. This article is protected by copyright. All rights reserved.