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Tumor suppressor and cerebral cortex development

Sergei Y Sokol
In this issue of Developmental Cell, Jossin et al. (2017) show that the tumor suppressor protein Lgl1 interacts with N-cadherin to stabilize apical junctions in brain stem cells. Neural progenitors lacking Lgl1 had decreased N-cadherin internalization and abnormal cell junctions, generating an ectopic neuronal layer that resembles cerebral cortex abnormalities in humans.
June 5, 2017: Developmental Cell
S Sreenivasa Reddy, Karnam Shruthi, V Sudhakar Reddy, G Raghu, P Suryanarayana, N V Giridharan, G Bhanuprakash Reddy
BACKGROUND: Obesity is associated with various progressive age-related diseases, including neurological disorders. However, underlying molecular basis for increased risk of neurodegeneration in obesity is unknown. A suitable animal model would immensely help in understanding the obesity-linked neurological problems. METHODS: A spontaneously developed obese rat (WNIN/Ob) which is highly vulnerable for a variety of degenerative diseases was isolated from the existing WNIN stock rats...
September 2014: Biochimica et Biophysica Acta
Mark A Zander, Sarah E Burns, Guang Yang, David R Kaplan, Freda D Miller
The Snail transcription factor plays a key role in regulating diverse developmental processes but is not thought to play a role in mammalian neural precursors. Here, we have examined radial glial precursor cells of the embryonic murine cortex and demonstrate that Snail regulates their survival, self-renewal, and differentiation into intermediate progenitors and neurons via two distinct and separable target pathways. First, Snail promotes cell survival by antagonizing a p53-dependent death pathway because coincident p53 knockdown rescues survival deficits caused by Snail knockdown...
April 9, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Meredith A Clifford, Wardah Athar, Carrie E Leonard, Alexandra Russo, Paul J Sampognaro, Marie-Sophie Van der Goes, Denver A Burton, Xiumei Zhao, Rupa R Lalchandani, Mustafa Sahin, Stefano Vicini, Maria J Donoghue
The process by which excitatory neurons are generated and mature during the development of the cerebral cortex occurs in a stereotyped manner; coordinated neuronal birth, migration, and differentiation during embryonic and early postnatal life are prerequisites for selective synaptic connections that mediate meaningful neurotransmission in maturity. Normal cortical function depends upon the proper elaboration of neurons, including the initial extension of cellular processes that lead to the formation of axons and dendrites and the subsequent maturation of synapses...
April 1, 2014: Proceedings of the National Academy of Sciences of the United States of America
Itsuki Ajioka
Once neurons enter the post-mitotic G0 phase during central nervous system (CNS) development, they lose their proliferative potential. When neurons re-enter the cell cycle during pathological situations such as neurodegeneration, they undergo cell death after S phase progression. Thus, the regulatory networks that drive cell proliferation and maintain neuronal differentiation are highly coordinated. In this review, the coordination of cell cycle control and neuronal differentiation during development are discussed, focusing on regulation by the Rb family of tumor suppressors (including p107 and p130), and the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitors...
June 2014: Development, Growth & Differentiation
Isidre Ferrer, Pooja Mohan, Helen Chen, Joan Castellsague, Laia Gómez-Baldó, Marga Carmona, Nadia García, Helena Aguilar, Jihong Jiang, Margaretha Skowron, Mark Nellist, Israel Ampuero, Antonio Russi, Conxi Lázaro, Christopher A Maxwell, Miguel Angel Pujana
Most patients with tuberous sclerosis complex (TSC) develop cortical tubers that cause severe neurological disabilities. It has been suggested that defects in neuronal differentiation and/or migration underlie the appearance of tubers. However, the precise molecular alterations remain largely unknown. Here, by combining cytological and immunohistochemical analyses of tubers from nine TSC patients (four of them diagnosed with TSC2 germline mutations), we show that alteration of microtubule biology through ROCK2 signalling contributes to TSC neuropathology...
July 2014: Journal of Pathology
Saida Ortolano, Irene Vieitez, Roberto Carlos Agis-Balboa, Carlos Spuch
BACKGROUND: Lafora disease is an autosomal recessive form of progressive myoclonic epilepsy caused by defects in the EPM2A and EPM2B genes. Primary symptoms of the pathology include seizures, ataxia, myoclonus, and progressive development of severe dementia. Lafora disease can be caused by defects in the EPM2A gene, which encodes the laforin protein phosphatase, or in the NHLRC1 gene (also called EPM2B) codifying the malin E3 ubiquitin ligase. Studies on cellular models showed that laforin and malin interact and operate as a functional complex apparently regulating cellular functions such as glycogen metabolism, cellular stress response, and the proteolytic processes...
2014: Molecular Brain
Sandrine L Anne, Eve-Ellen Govek, Olivier Ayrault, Jee Hae Kim, Xiaodong Zhu, David A Murphy, Linda Van Aelst, Martine F Roussel, Mary E Hatten
During normal cerebellar development, the remarkable expansion of granule cell progenitors (GCPs) generates a population of granule neurons that outnumbers the total neuronal population of the cerebral cortex, and provides a model for identifying signaling pathways that may be defective in medulloblastoma. While many studies focus on identifying pathways that promote growth of GCPs, a critical unanswered question concerns the identification of signaling pathways that block mitogenic stimulation and induce early steps in differentiation...
2013: PloS One
Yuriko Nishizaki, Tsuyoshi Takagi, Fumiko Matsui, Yujiro Higashi
A loss of function of SIP1 (Smad interacting protein 1) in the mouse as well as in human of Mowat-Wilson syndrome results in severe and multiple defects in neural tissue development, especially in the brain. However, no detailed expression analysis of SIP1 during brain development has been previously reported. In this study, we describe the generation of an EGFP knock-in reporter mouse for the Sip1 locus and our subsequent analysis of SIP1-EGFP fusion protein expression during brain development. SIP1-EGFP expression was observed in the pyramidal neurons of the hippocampus, the dentate gyrus, and the postmitotic neurons in the cerebral cortex...
January 2014: Genesis: the Journal of Genetics and Development
Anna Noren Rubin, Nicoletta Kessaris
The homeobox-encoding gene Prox1 and its Drosophila homologue prospero are key regulators of cell fate-specification. In the developing rodent cortex a sparse population of cells thought to correspond to late-generated cortical pyramidal neuron precursors expresses PROX1. Using a series of transgenic mice that mark cell lineages in the subcortical telencephalon and, more specifically, different populations of cortical interneurons, we demonstrate that neurons expressing PROX1 do not represent pyramidal neurons or their precursors but are instead subsets of cortical interneurons...
2013: PloS One
Marion Dubuissez, Perrine Faiderbe, Sébastien Pinte, Vanessa Dehennaut, Brian R Rood, Dominique Leprince
The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) is located in 17p13.3 a region frequently hypermethylated or deleted in tumors and in a contiguous-gene syndrome, the Miller-Dieker syndrome which includes classical lissencephaly (smooth brain) and severe developmental defects. HIC1 encodes a transcriptional repressor involved in the regulation of growth control, DNA damage response and cell migration properties. We previously demonstrated that the membrane-associated G-protein-coupled receptors CXCR7, ADRB2 and the tyrosine kinase receptor EphA2 are direct target genes of HIC1...
October 25, 2013: Biochemical and Biophysical Research Communications
Silvia Cappello, Mary J Gray, Caroline Badouel, Simona Lange, Melanie Einsiedler, Myriam Srour, David Chitayat, Fadi F Hamdan, Zandra A Jenkins, Tim Morgan, Nadia Preitner, Tami Uster, Jackie Thomas, Patrick Shannon, Victoria Morrison, Nataliya Di Donato, Lionel Van Maldergem, Teresa Neuhann, Ruth Newbury-Ecob, Marielle Swinkells, Paulien Terhal, Louise C Wilson, Petra J G Zwijnenburg, Andrew J Sutherland-Smith, Michael A Black, David Markie, Jacques L Michaud, Michael A Simpson, Sahar Mansour, Helen McNeill, Magdalena Götz, Stephen P Robertson
The regulated proliferation and differentiation of neural stem cells before the generation and migration of neurons in the cerebral cortex are central aspects of mammalian development. Periventricular neuronal heterotopia, a specific form of mislocalization of cortical neurons, can arise from neuronal progenitors that fail to negotiate aspects of these developmental processes. Here we show that mutations in genes encoding the receptor-ligand cadherin pair DCHS1 and FAT4 lead to a recessive syndrome in humans that includes periventricular neuronal heterotopia...
November 2013: Nature Genetics
Chris M Egan, Ulrika Nyman, Julie Skotte, Gundula Streubel, Siobhán Turner, David J O'Connell, Vilma Rraklli, Michael J Dolan, Naomi Chadderton, Klaus Hansen, Gwyneth Jane Farrar, Kristian Helin, Johan Holmberg, Adrian P Bracken
The chromatin remodeler CHD5 is expressed in neural tissue and is frequently deleted in aggressive neuroblastoma. Very little is known about the function of CHD5 in the nervous system or its mechanism of action. Here we report that depletion of Chd5 in the developing neocortex blocks neuronal differentiation and leads to an accumulation of undifferentiated progenitors. CHD5 binds a large cohort of genes and is required for facilitating the activation of neuronal genes. It also binds a cohort of Polycomb targets and is required for the maintenance of H3K27me3 on these genes...
August 12, 2013: Developmental Cell
Jennifer Betancourt, Sol Katzman, Bin Chen
During development of the cerebral cortex, neural stem cells divide to expand the progenitor pool and generate basal progenitors, outer radial glia, and cortical neurons. As these newly born neurons differentiate, they must properly migrate toward their final destination in the cortical plate, project axons to appropriate targets, and develop dendrites. However, a complete understanding of the precise genetic mechanisms regulating these steps is lacking. Here we show that a member of the nuclear factor one (NFI) family of transcription factors, NFIB, is essential for many of these processes in mice...
January 1, 2014: Journal of Comparative Neurology
Laura Magri, Manuela Cominelli, Marco Cambiaghi, Marco Cursi, Letizia Leocani, Fabio Minicucci, Pietro Luigi Poliani, Rossella Galli
Tuberous sclerosis complex (TSC) is a dominantly inherited disease with high penetrance and morbidity, and is caused by mutations in either of two genes, TSC1 or TSC2. Most affected individuals display severe neurological manifestations - such as intractable epilepsy, mental retardation and autism - that are intimately associated with peculiar CNS lesions known as cortical tubers (CTs). The existence of a significant genotype-phenotype correlation in individuals bearing mutations in either TSC1 or TSC2 is highly controversial...
September 2013: Disease Models & Mechanisms
Elizabeth A Normand, Shane R Crandall, Catherine A Thorn, Emily M Murphy, Bettina Voelcker, Catherine Browning, Jason T Machan, Christopher I Moore, Barry W Connors, Mark Zervas
Tuberous sclerosis is a developmental genetic disorder caused by mutations in TSC1, which results in epilepsy, autism, and intellectual disability. The cause of these neurological deficits remains unresolved. Imaging studies suggest that the thalamus may be affected in tuberous sclerosis patients, but this has not been experimentally interrogated. We hypothesized that thalamic deletion of Tsc1 at distinct stages of mouse brain development would produce differential phenotypes. We show that mosaic Tsc1 deletion within thalamic precursors at embryonic day (E) 12...
June 5, 2013: Neuron
Samantha M Lloyd-Burton, Elisa M York, Mohammad A Anwar, Adele J Vincent, A Jane Roskams
Secreted protein acidic rich in cysteine (SPARC) is a matricellular protein that modulates the activity of growth factors, cytokines, and extracellular matrix to play multiple roles in tissue development and repair, such as cellular adhesion, migration, and proliferation. Throughout the CNS, SPARC is highly localized in mature ramified microglia, but its role in microglia--in development or during response to disease or injury--is not understood. In the postnatal brain, immature amoeboid myeloid precursors only induce SPARC expression after they cease proliferation and migration, and transform into mature, ramified resting microglia...
March 6, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Rebecca D Hodge, Alfredo J Garcia, Gina E Elsen, Branden R Nelson, Kristin E Mussar, Steven L Reiner, Jan-Marino Ramirez, Robert F Hevner
The dentate gyrus (DG) is a unique cortical region whose protracted development spans the embryonic and early postnatal periods. DG development involves large-scale reorganization of progenitor cell populations, ultimately leading to the establishment of the subgranular zone neurogenic niche. In the developing DG, the T-box transcription factor Tbr2 is expressed in both Cajal-Retzius cells derived from the cortical hem that guide migration of progenitors and neurons to the DG, and intermediate neuronal progenitors born in the dentate neuroepithelium that give rise to granule neurons...
February 27, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jonathan DeGeer, Jérôme Boudeau, Susanne Schmidt, Fiona Bedford, Nathalie Lamarche-Vane, Anne Debant
The chemotropic guidance cue netrin-1 mediates attraction of migrating axons during central nervous system development through the receptor Deleted in Colorectal Cancer (DCC). Downstream of netrin-1, activated Rho GTPases Rac1 and Cdc42 induce cytoskeletal rearrangements within the growth cone. The Rho guanine nucleotide exchange factor (GEF) Trio is essential for Rac1 activation downstream of netrin-1/DCC, but the molecular mechanisms governing Trio activity remain elusive. Here, we demonstrate that Trio is phosphorylated by Src family kinases in the embryonic rat cortex in response to netrin-1...
February 2013: Molecular and Cellular Biology
Timothy D Myshrall, Steven A Moore, Adam P Ostendorf, Jakob S Satz, Tom Kowalczyk, Huy Nguyen, Ray A M Daza, Charmaine Lau, Kevin P Campbell, Robert F Hevner
Interactions between the embryonic pial basement membrane (PBM) and radial glia (RG) are essential for morphogenesis of the cerebral cortex because disrupted interactions cause cobblestone malformations. To elucidate the role of dystroglycan (DG) in PBM-RG interactions, we studied the expression of DG protein and Dag1 mRNA (which encodes DG protein) in developing cerebral cortex and analyzed cortical phenotypes in Dag1 CNS conditional mutant mice. In normal embryonic cortex, Dag1 mRNA was expressed in the ventricular zone, which contains RG nuclei, whereas DG protein was expressed at the cortical surface on RG end feet...
December 2012: Journal of Neuropathology and Experimental Neurology
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