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Hyejung Won, Luis de la Torre-Ubieta, Jason L Stein, Neelroop N Parikshak, Jerry Huang, Carli K Opland, Michael J Gandal, Gavin J Sutton, Farhad Hormozdiari, Daning Lu, Changhoon Lee, Eleazar Eskin, Irina Voineagu, Jason Ernst, Daniel H Geschwind
Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner. However, the 3D organization of chromosomes during human brain development and its role in regulating gene networks dysregulated in neurodevelopmental disorders, such as autism or schizophrenia, are unknown. Here we generate high-resolution 3D maps of chromatin contacts during human corticogenesis, permitting large-scale annotation of previously uncharacterized regulatory relationships relevant to the evolution of human cognition and disease...
October 19, 2016: Nature
E Sacide Çağlayan
Dual-specificity thyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a strong therapeutic target to ameliorate cognitive functions of Down Syndrome (DS). Genetic normalization of Dyrk1a is sufficient to normalize early cortical developmental phenotypes in DS mouse models. Gyrencephalic human neocortical development is more complex than that in lissencephalic mice, hence cerebral organoids (COs) can be used to model early neurodevelopmental defects of DS. Single copy DYRK1A knockout COs (scDYRK1AKO-COs) can be generated from manipulated DS derived (DS-) induced pluripotent stem cells (iPSCs) and genetic normalization of DYRK1A is expected to result in corrected neurodevelopmental phenotypes that can be reminiscent of normal COs...
October 15, 2016: Cell Biology International
A-Ram Lee, Kwang Woo Ko, Hojae Lee, Yi-Seul Yoon, Mi-Ryoung Song, Chul-Seung Park
UNLABELLED: During brain development, dynamic changes in neuronal membranes perform critical roles in neuronal morphogenesis and migration to create functional neural circuits. Among the proteins that induce membrane dynamics, cell adhesion molecules are important in neuronal membrane plasticity. Here, we report that V-set and transmembrane domain-containing protein 5 (Vstm5), a cell-adhesion-like molecule belonging to the Ig superfamily, was found in mouse brain. Knock-down of Vstm5 in cultured hippocampal neurons markedly reduced the complexity of dendritic structures, as well as the number of dendritic filopodia...
September 28, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Bing Lang, Lei Zhang, Guanyu Jiang, Ling Hu, Wei Lan, Lei Zhao, Irene Hunter, Michal Pruski, Ning-Ning Song, Ying Huang, Ling Zhang, David St Clair, Colin D McCaig, Yu-Qiang Ding
Schizophrenia is a debilitating familial neuropsychiatric disorder which affects 1% of people worldwide. Although the heritability for schizophrenia approaches 80% only a small proportion of the overall genetic risk has been accounted for, and to date only a limited number of genetic loci have been definitively implicated. We have identified recently through genetic and in vitro functional studies, a novel serine/threonine kinase gene, unc-51-like kinase 4 (ULK4), as a rare risk factor for major mental disorders including schizophrenia...
September 27, 2016: Scientific Reports
Tally Lerman-Sagie, Zvi Leibovitz
Abnormal fetal corticogenesis results in malformations of cortical development (MCD). Abnormal cell proliferation leads to microcephaly or megalencephaly, incomplete neuronal migration results in heterotopia and lissencephaly, neuronal overmigration manifests as cobblestone malformations, and anomalous postmigrational cortical organization is responsible for polymicrogyria and focal cortical dysplasias. MCD comprises various congenital brain disorders, caused by different genetic, infectious, or vascular etiologies and is associated with significant neurological morbidity...
September 2016: Canadian Journal of Neurological Sciences. le Journal Canadien des Sciences Neurologiques
Marion Betizeau, Colette Dehay
It has been hypothesized that the higher number of neurons in human cortex compared to the chimpanzee and other primate species is key to high cognitive function. Are human cortical precursors endowed with specific properties that drive greater neuronal expansion than in other non-human primates? Otani et al. 2016 addressed this issue taking advantage of comparative in vitro corticogenesis models based on human, chimpanzee and macaque pluripotent stem cells. Clonal analysis revealed a heterochrony of early developmental events possibly leading to a relatively higher expansion of human cortical precursor population...
2016: Stem Cell Investigation
Tiffany V Lin, Lawrence Hsieh, Tomoki Kimura, Taylor J Malone, Angélique Bordey
Hyperactive mammalian target of rapamycin complex 1 (mTORC1) is a shared molecular hallmark in several neurodevelopmental disorders characterized by abnormal brain cytoarchitecture. The mechanisms downstream of mTORC1 that are responsible for these defects remain unclear. We show that focally increasing mTORC1 activity during late corticogenesis leads to ectopic placement of upper-layer cortical neurons that does not require altered signaling in radial glia and is accompanied by changes in layer-specific molecular identity...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
Betty Freret-Hodara, Yi Cui, Amélie Griveau, Lisa Vigier, Yoko Arai, Jonathan Touboul, Alessandra Pierani
Loss of neurons in the neocortex is generally thought to result in a final reduction of cerebral volume. Yet, little is known on how the developing cerebral cortex copes with death of early-born neurons. Here, we tackled this issue by taking advantage of a transgenic mouse model in which, from early embryonic stages to mid-corticogenesis, abundant apoptosis is induced in the postmitotic compartment. Unexpectedly, the thickness of the mutant cortical plate at E18.5 was normal, due to an overproduction of upper layer neurons at E14...
September 12, 2016: Cerebral Cortex
Yutaka Inaguma, Ayumi Matsumoto, Mariko Noda, Hidenori Tabata, Akihiko Maeda, Masahide Goto, Daisuke Usui, Eriko F Jimbo, Kiyoshi Kikkawa, Mamitaro Ohtsuki, Mariko Y Momoi, Hitoshi Osaka, Takanori Yamagata, Koh-Ichi Nagata
Class III phosphoinositide 3-kinase (PIK3C3 or mammalian vacuolar protein sorting 34 homolog, Vps34) regulates vesicular trafficking, autophagy, and nutrient sensing. Recently, we reported that PIK3C3 is expressed in mouse cerebral cortex throughout the developmental process, especially at early embryonic stage. We thus examined the role of PIK3C3 in the development of the mouse cerebral cortex. Acute silencing of PIK3C3 with in utero electroporation method caused positional defects of excitatory neurons during corticogenesis...
October 2016: Journal of Neurochemistry
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
Hiroyuki Koizumi, Hiromi Fujioka, Kazuya Togashi, James Thompson, John R Yates, Joseph G Gleeson, Kazuo Emoto
Doublecortin-like kinase 1 (DCLK1) is a member of the neuronal microtubule-associated doublecortin (DCX) family and functions in multiple stages of neural development including radial migration and axon growth of cortical neurons. DCLK1 is suggested to play the roles in part through its protein kinase activity, yet the kinase substrates of DCLK1 remain largely unknown. Here we have identified MAP7D1 (microtubule-associated protein 7 domain containing 1) as a novel substrate of DCLK1 by using proteomic analysis...
August 9, 2016: Developmental Neurobiology
Jihane Homman-Ludiye, James A Bourne
Throughout evolution, the neocortex has undergone a dramatic expansion providing the substrate for increasingly complex cognitive abilities, culminating with humans. The enlargement of the neocortex did not affect its' basic organization, which is remarkably conserved from rodents to primates. The mouse has thus proven an advantageous model to decipher the molecular and cellular mechanisms supporting neocortical development. However, it is of limited benefit when studying the mechanisms leading to the inclusion of higher-order association areas, which form the largest fraction of the primate neocortex...
August 1, 2016: Developmental Neurobiology
Ross Ferguson, Eleni Serafeimidou-Pouliou, Vasanta Subramanian
The hexanucleotide repeat in the first intron of the C9orf72 gene is the most significant cause of amyotropic lateral sclerosis as well as some forms of fronto-temporal dementia. The C9orf72 protein has been previously reported to be expressed in post-mortem human brain as well as in late embryonic and some postnatal stages in mice. Herein, we present a detailed study of the distribution of C9orf72 protein in the embryonic, postnatal and adult mouse brain, spinal cord as well as during the differentiation of P19 embryonal carcinoma cells to neurons including motor neurons...
August 1, 2016: Journal of Anatomy
Munekazu Komada, Yuuya Gendai, Nao Kagawa, Tetsuji Nagao
Di(2-ethylhexyl) phthalate (DEHP) is currently the most commonly used phthalate for the production of flexible polyvinyl chloride. Phthalates including DEHP have been labeled as potential endocrine disruptors. The effect on the development of the neocortex, however, is unknown. To evaluate the neurodevelopmental effects of prenatal DEHP exposure at 1 and 100mg/kg/day or 100 and 500mg/kg/day in fetal and newborn mice, we performed a detailed histologic analysis of the developing dorsal telencephalon and neocortex...
September 30, 2016: Toxicology Letters
Yohei Bamba, Tomoko Shofuda, Mitsuhiro Kato, Ritsuko K Pooh, Yoko Tateishi, Jun-Ichi Takanashi, Hidetsuna Utsunomiya, Miho Sumida, Daisuke Kanematsu, Hiroshi Suemizu, Yuichiro Higuchi, Wado Akamatsu, Denis Gallagher, Freda D Miller, Mami Yamasaki, Yonehiro Kanemura, Hideyuki Okano
BACKGROUND: Lissencephaly, or smooth brain, is a severe congenital brain malformation that is thought to be associated with impaired neuronal migration during corticogenesis. However, the exact etiology of lissencephaly in humans remains unknown. Research on congenital diseases is limited by the shortage of clinically derived resources, especially for rare pediatric diseases. The research on lissencephaly is further limited because gyration in humans is more evolved than that in model animals such as mice...
2016: Molecular Brain
Pei-Shan Wang, Fu-Sheng Chou, Sreekumar Ramachandran, Sheng Xia, Huei-Ying Chen, Fengli Guo, Praveen Suraneni, Brady J Maher, Rong Li
The polarity and organization of radial glial cells (RGCs), which serve as both stem cells and scaffolds for neuronal migration, are crucial for cortical development. However, the cytoskeletal mechanisms that drive radial glial outgrowth and maintain RGC polarity remain poorly understood. Here, we show that the Arp2/3 complex - the unique actin nucleator that produces branched actin networks - plays essential roles in RGC polarity and morphogenesis. Disruption of the Arp2/3 complex in murine RGCs retards process outgrowth toward the basal surface and impairs apical polarity and adherens junctions...
August 1, 2016: Development
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
Anton B Tonchev, Tran Cong Tuoc, Eva H Rosenthal, Michèle Studer, Anastassia Stoykova
BACKGROUND: During corticogenesis, genetic programs encoded in progenitor cells at different developmental stages and inherited in postmitotic neurons specify distinct layer and area identities. Transcription factor Zbtb20 has been shown to play a role for hippocampal development but whether it is implicated in mammalian neocortical morphogenesis remains unknown. RESULTS: Here, we report that during embyogenesis transcription factor Zbtb20 has a dynamic spatio-temporal expression pattern in mitotic cortical progenitors through which it modulates the sequential generation of cortical neuronal layer identities...
2016: Molecular Brain
Melina Rapacioli, Verónica Palma, Vladimir Flores
[This corrects the article on p. 67 in vol. 10, PMID: 27013978.].
2016: Frontiers in Cellular Neuroscience
Chiaki Ohtaka-Maruyama, Kazunori Nakajima, Alessandra Pierani, Nobuaki Maeda
No abstract text is available yet for this article.
2016: Frontiers in Neuroscience
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