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A Mateus-Pinheiro, N D Alves, P Patrício, A R Machado-Santos, E Loureiro-Campos, J M Silva, V M Sardinha, J Reis, H Schorle, J F Oliveira, J Ninkovic, N Sousa, L Pinto
Hippocampal neurogenesis has been proposed to participate in a myriad of behavioral responses, both in basal states and in the context of neuropsychiatric disorders. Here, we identify activating protein 2γ (AP2γ, also known as Tcfap2c), originally described to regulate the generation of neurons in the developing cortex, as a modulator of adult hippocampal glutamatergic neurogenesis in mice. Specifically, AP2γ is present in a sub-population of hippocampal transient amplifying progenitors. There, it is found to act as a positive regulator of the cell fate determinants Tbr2 and NeuroD, promoting proliferation and differentiation of new glutamatergic granular neurons...
October 25, 2016: Molecular Psychiatry
Samah Kalakh, Abdeslam Mouihate
There is compelling evidence that microglial activation negatively impacts neurogenesis. However, microglia have also been shown to promote recruitment of newly born neurons to injured areas of the gray matter. In the present study, we explored whether demyelination-triggered inflammation alters the process of neurogenesis in the white matter. A 2-μl solution of 0.04 % ethidium bromide was stereotaxically injected into the corpus callosum of adult male rats. Brain inflammation was dampened by daily injections of progesterone (5 mg/kg, s...
September 23, 2016: Molecular Neurobiology
Alessandro Sessa, Ernesto Ciabatti, Daniela Drechsel, Luca Massimino, Gaia Colasante, Serena Giannelli, Takashi Satoh, Shizuo Akira, Francois Guillemot, Broccoli Vania
The T-box containing Tbr2 gene encodes for a transcription factor essential for the specification of the intermediate neural progenitors (INPs) originating the excitatory neurons of the cerebral cortex. However, its overall mechanism of action, direct target genes and cofactors remain unknown. Herein, we carried out global gene expression profiling combined with genome-wide binding site identification to determine the molecular pathways regulated by TBR2 in INPs. This analysis led to the identification of novel protein-protein interactions that control multiple features of INPs including cell-type identity, morphology, proliferation and migration dynamics...
September 6, 2016: Cerebral Cortex
Joanna Yeung, Thomas J Ha, Douglas J Swanson, Dan Goldowitz
UNLABELLED: Pax6 is a prominent gene in brain development. The deletion of Pax6 results in devastated development of eye, olfactory bulb, and cortex. However, it has been reported that the Pax6-null Sey cerebellum only has minor defects involving granule cells despite Pax6 being expressed throughout cerebellar development. The present work has uncovered a requirement of Pax6 in the development of all rhombic lip (RL) lineages. A significant downregulation of Tbr1 and Tbr2 expression is found in the Sey cerebellum, these are cell-specific markers of cerebellar nuclear (CN) neurons and unipolar brush cells (UBCs), respectively...
August 31, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Martin Raasch, Knut Rennert, Tobias Jahn, Claudia Gärtner, Gilbert Schönfelder, Otmar Huber, Andrea E M Seiler, Alexander S Mosig
The development of therapeutic substances to treat diseases of the central nervous system is hampered by the tightness and selectivity of the blood-brain barrier. Moreover, testing of potential drugs is time-consuming and cost-intensive. Here, we established a new microfluidically supported, biochip-based model of the brain endothelial barrier in combination with brain cortical spheroids suitable to detect effects of neuroinflammation upon disruption of the endothelial layer in response to inflammatory signals...
July 2016: Biomicrofluidics
Tomohisa Toda, Yohei Shinmyo, Tung Anh Dinh Duong, Kosuke Masuda, Hiroshi Kawasaki
Because folding of the cerebral cortex in the mammalian brain is believed to be crucial for higher brain functions, the mechanisms underlying its formation during development and evolution are of great interest. Although it has been proposed that increased neural progenitors in the subventricular zone (SVZ) are responsible for making cortical folds, their roles in cortical folding are still largely unclear, mainly because genetic methods for gyrencephalic mammals had been poorly available. Here, by taking an advantage of our newly developed in utero electroporation technique for the gyrencephalic brain of ferrets, we investigated the role of SVZ progenitors in cortical folding...
2016: Scientific Reports
Cong Sui, Ezekiel Mecha, Charles Oa Omwandho, Anna Starzinski-Powitz, Angelika Stammler, Hans-Rudolf Tinneberg, Lutz Konrad
In the endometrium transforming growth factor-betas (TGF-βs) are involved mainly in menstruation and endometriosis. After binding of the ligands to the high-affinity receptors, TGF-β receptors (TBR1 and TBR2), TGF-βs activate Smad signaling to modulate gene expression and cellular functions. However, recently also Smad-independent pathways have been studied in more details. To evaluate both pathways, we have analyzed TGF-β signaling in human endometrial and endometriotic cells. Although endometrial and endometriotic cells secrete TGF-β1, secretion by stromal cells was higher compared to epithelial cells...
2016: American Journal of Translational Research
Takeshi Tanaka, Yasuko Hasegawa-Baba, Yousuke Watanabe, Sayaka Mizukami, Yumi Kangawa, Toshinori Yoshida, Makoto Shibutani
To elucidate the developmental exposure effects of ochratoxin A (OTA) on postnatal hippocampal neurogenesis, pregnant SD rats were provided a diet containing 0, 0.12, 0.6, or 3.0ppm OTA from gestation day 6 to day 21 on weaning after delivery. Offspring were maintained through postnatal day (PND) 77 without OTA exposure. At 3.0ppm, offspring of both sexes showed a transient body weight decrease after weaning. Changes in hippocampal neurogenesis-related parameters as measured in male PND 21 offspring were observed at 3...
June 23, 2016: Reproductive Toxicology
Anca B Mihalas, Gina E Elsen, Francesco Bedogni, Ray A M Daza, Kevyn A Ramos-Laguna, Sebastian J Arnold, Robert F Hevner
Intermediate progenitors (IPs) amplify the production of pyramidal neurons, but their role in selective genesis of cortical layers or neuronal subtypes remains unclear. Using genetic lineage tracing in mice, we find that IPs destined to produce upper cortical layers first appear early in corticogenesis, by embryonic day 11.5. During later corticogenesis, IP laminar fates are progressively limited to upper layers. We examined the role of Tbr2, an IP-specific transcription factor, in laminar fate regulation using Tbr2 conditional mutant mice...
June 28, 2016: Cell Reports
Vanesa Nieto-Estévez, Carlos O Oueslati-Morales, Lingling Li, James Pickel, Aixa V Morales, Carlos Vicario-Abejón
The specific actions of insulin-like growth factor-I (IGF-I) and the role of brain-derived IGF-I during hippocampal neurogenesis have not been fully defined. To address the influence of IGF-I on the stages of hippocampal neurogenesis, we studied a postnatal/adult global Igf-I knockout (KO) mice (Igf-I(-/-) ) and a nervous system Igf-I conditional KO (Igf-I(Δ/Δ) ). In both KO mice we found an accumulation of Tbr2(+) -intermediate neuronal progenitors, some of which were displaced in the outer granule cell layer (GCL) and the molecular layer (ML) of the dentate gyrus (DG)...
August 2016: Stem Cells
Cecilia I Lopez, Katherine E Saud, Rodrigo Aguilar, F Andrés Berndt, José Cánovas, Martín Montecino, Manuel Kukuljan
The development of the cerebral cortex is a dynamic and coordinated process in which cell division, cell death, migration and differentiation must be highly regulated to acquire the final architecture and functional competence of the mature organ. Notch pathway is an important regulator of differentiation and it is essential to maintain neural stem cell (NSC) pool. Here we studied the role of epigenetic modulators such as lysine-specific demethylase 1 (LSD1) and its interactor CoREST in the regulation of the Notch pathway activity during the development of the cerebral cortex...
April 25, 2016: Developmental Neurobiology
H Belinson, J Nakatani, B A Babineau, R Y Birnbaum, J Ellegood, M Bershteyn, R J McEvilly, J M Long, K Willert, O D Klein, N Ahituv, J P Lerch, M G Rosenfeld, A Wynshaw-Boris
Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a β-catenin/Brn2/Tbr2 transcriptional cascade...
October 2016: Molecular Psychiatry
Amanjot Kaur Riar, Madhusudhanan Narasimhan, Mary Latha Rathinam, George I Henderson, Lenin Mahimainathan
BACKGROUND: Developing brain is a major target for alcohol's actions and neurological/functional abnormalities include microencephaly, reduced frontal cortex, mental retardation and attention-deficits. Previous studies have shown that ethanol altered the lateral ventricular neuroepithelial cell proliferation. However, the effect of ethanol on subventricular basal progenitors which generate majority of the cortical layers is not known. METHODS: We utilized spontaneously immortalized rat brain neuroblasts obtained from cultures of 18-day-old fetal rat cerebral cortices using in vitro ethanol exposures and an in utero binge model...
2016: Journal of Biomedical Science
Nereo Kalebic, Elena Taverna, Stefania Tavano, Fong Kuan Wong, Dana Suchold, Sylke Winkler, Wieland B Huttner, Mihail Sarov
We have applied the CRISPR/Cas9 system in vivo to disrupt gene expression in neural stem cells in the developing mammalian brain. Two days after in utero electroporation of a single plasmid encoding Cas9 and an appropriate guide RNA (gRNA) into the embryonic neocortex of Tis21::GFP knock-in mice, expression of GFP, which occurs specifically in neural stem cells committed to neurogenesis, was found to be nearly completely (≈ 90%) abolished in the progeny of the targeted cells. Importantly, upon in utero electroporation directly of recombinant Cas9/gRNA complex, near-maximal efficiency of disruption of GFP expression was achieved already after 24 h...
March 2016: EMBO Reports
Ashlie A Tronnes, Jenna Koschnitzky, Ray Daza, Jane Hitti, Jan Marino Ramirez, Robert Hevner
Our objective was to determine if progesterone pretreatment could ameliorate the detrimental effects of lipopolysaccharide (LPS)-induced inflammation on cortical neurogenesis. Timed pregnant mouse dams (n = 8) were given intraperitoneal injections of progesterone (42 mg/kg) or vehicle on embryonic day 17.5. Two hours later, mice were given intraperitoneal LPS (140 μg/kg) or vehicle. Mice were sacrificed 16 hours later on embryonic day 18. Two-color immunofluorescence was performed with primary antibodies T-box transcription factor 2 (Tbr2), ionized calcium binding adapter molecule 1 (Iba1), cleaved caspase 3 (CC3), and 5-bromo-2'-deoxyuridine (BrdU)...
June 2016: Reproductive Sciences
Sara Cipriani, Nathalie Journiac, Jeannette Nardelli, Catherine Verney, Anne-Lise Delezoide, Fabien Guimiot, Pierre Gressens, Homa Adle-Biassette
The molecular mechanisms that orchestrate the development of the human dentate gyrus are not known. In this study, we characterized the formation of human dentate and fimbrial progenitors and postmitotic neurons from 9 gestational weeks (GW9) to GW25. PAX6(+) progenitor cells remained proliferative until GW16 in the dentate ventricular zone. By GW11, the secondary dentate matrix had developed in the intermediate zone, surrounding the dentate anlage and streaming toward the subpial layer. This secondary matrix contained proliferating PAX6(+) and/or TBR2(+) progenitors...
October 5, 2015: Cerebral Cortex
Takeshi Tanaka, Hajime Abe, Masayuki Kimura, Nobuhiko Onda, Sayaka Mizukami, Toshinori Yoshida, Makoto Shibutani
To determine the developmental exposure effects of T-2 toxin on postnatal hippocampal neurogenesis, pregnant ICR mice were provided a diet containing T-2 toxin at 0, 1, 3, or 9 ppm from gestation day 6 to day 21 on weaning after delivery. Offspring were maintained through postnatal day (PND) 77 without T-2 toxin exposure. In the hippocampal dentate gyrus of male PND 21 offspring, GFAP(+) and BLBP(+) type-1 stem cells and PAX6(+) and TBR2(+) type-2 progenitor cells decreased in the subgranular zone (SGZ) at 9 and ≥3 ppm, respectively, in parallel with increased apoptosis at ≥3 ppm...
August 2016: Archives of Toxicology
Priya Srikanth, Karam Han, Dana G Callahan, Eugenia Makovkina, Christina R Muratore, Matthew A Lalli, Honglin Zhou, Justin D Boyd, Kenneth S Kosik, Dennis J Selkoe, Tracy L Young-Pearse
Genetic and clinical association studies have identified disrupted in schizophrenia 1 (DISC1) as a candidate risk gene for major mental illness. DISC1 is interrupted by a balanced chr(1;11) translocation in a Scottish family in which the translocation predisposes to psychiatric disorders. We investigate the consequences of DISC1 interruption in human neural cells using TALENs or CRISPR-Cas9 to target the DISC1 locus. We show that disruption of DISC1 near the site of the translocation results in decreased DISC1 protein levels because of nonsense-mediated decay of long splice variants...
September 1, 2015: Cell Reports
Christian B Brøchner, Kjeld Møllgård
The glycosphingolipid SSEA-4 and the glycoprotein YKL-40 have both been associated with human embryonic and neural stem cell differentiation. We investigated the distribution of SSEA-4 and YKL-40 positive cells in proliferative zones of human fetal forebrain using immunohistochemistry and double-labeling immunofluorescence. A few small rounded SSEA-4 and YKL-40 labeled cells were present in the radial glial BLBP positive proliferative zones adjacent to the lateral ganglionic eminence from 12th week post conception...
January 2016: Glia
Verónica Martínez-Cerdeño, Christopher L Cunningham, Jasmin Camacho, Janet A Keiter, Jeanelle Ariza, Matthew Lovern, Stephen C Noctor
The subventricular zone (SVZ) is greatly expanded in primates with gyrencephalic cortices and is thought to be absent from vertebrates with three-layered, lissencephalic cortices, such as the turtle. Recent work in rodents has shown that Tbr2-expressing neural precursor cells in the SVZ produce excitatory neurons for each cortical layer in the neocortex. Many excitatory neurons are generated through a two-step process in which Pax6-expressing radial glial cells divide in the VZ to produce Tbr2-expressing intermediate progenitor cells, which divide in the SVZ to produce cortical neurons...
February 15, 2016: Journal of Comparative Neurology
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