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      ANO1/TMEM16A regulates process maturation in radial glial cells in the developing brain

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          Radial glial cells (RGCs), a type of neural stem cell in the developing brain, not only generate progenitors, newly born neurons and glial cells, but also deliver neurons through its process to the appropriate cortical target layers. Thus, the function of RGCs is crucial for cortex development, in which Cl channels are thought to play a role. Here we highlight that Anoctamin 1 (ANO1)/TMEM16A, a Ca 2+-activated Cl channel, mediates the process extension in RGCs. ANO1-null mice show a decrease in cortical thickness with disorganized cortical layers. Thus, as a Cl channel, ANO1 is involved in the process maturation of RGCs and contributes to cortex development.


          Neural stem cells (NSCs) are primary progenitor cells in the early developmental stage in the brain that initiate a diverse lineage of differentiated neurons and glia. Radial glial cells (RGCs), a type of neural stem cell in the ventricular zone, are essential for nurturing and delivering new immature neurons to the appropriate cortical target layers. Here we report that Anoctamin 1 (ANO1)/TMEM16A, a Ca 2+-activated chloride channel, mediates the Ca 2+-dependent process extension of RGCs. ANO1 is highly expressed and functionally active in RGCs of the mouse embryonic ventricular zone. Knockdown of ANO1 suppresses RGC process extension and protrusions, whereas ANO1 overexpression stimulates process extension. Among various trophic factors, brain-derived neurotrophic factor (BDNF) activates ANO1, which is required for BDNF-induced process extension in RGCs. More importantly, Ano1-deficient mice exhibited disrupted cortical layers and reduced cortical thickness. We thus conclude that the regulation of RGC process extension by ANO1 contributes to the normal formation of mouse embryonic brain.

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          Most cited references 45

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          The glial nature of embryonic and adult neural stem cells.

          Glial cells were long considered end products of neural differentiation, specialized supportive cells with an origin very different from that of neurons. New studies have shown that some glial cells--radial glia (RG) in development and specific subpopulations of astrocytes in adult mammals--function as primary progenitors or neural stem cells (NSCs). This is a fundamental departure from classical views separating neuronal and glial lineages early in development. Direct visualization of the behavior of NSCs and lineage-tracing studies reveal how neuronal lineages emerge. In development and in the adult brain, many neurons and glial cells are not the direct progeny of NSCs, but instead originate from transit amplifying, or intermediate, progenitor cells (IPCs). Within NSCs and IPCs, genetic programs unfold for generating the extraordinary diversity of cell types in the central nervous system. The timing in development and location of NSCs, a property tightly linked to their neuroepithelial origin, appear to be the key determinants of the types of neurons generated. Identification of NSCs and IPCs is critical to understand brain development and adult neurogenesis and to develop new strategies for brain repair.
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            Neuronal subtype specification in the cerebral cortex.

            In recent years, tremendous progress has been made in understanding the mechanisms underlying the specification of projection neurons within the mammalian neocortex. New experimental approaches have made it possible to identify progenitors and study the lineage relationships of different neocortical projection neurons. An expanding set of genes with layer and neuronal subtype specificity have been identified within the neocortex, and their function during projection neuron development is starting to be elucidated. Here, we assess recent data regarding the nature of neocortical progenitors, review the roles of individual genes in projection neuron specification and discuss the implications for progenitor plasticity.
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              Evolution of the neocortex: a perspective from developmental biology.

               Pasko Rakic (2009)
              The enlargement and species-specific elaboration of the cerebral neocortex during evolution holds the secret to the mental abilities of humans; however, the genetic origin and cellular mechanisms that generated the distinct evolutionary advancements are not well understood. This article describes how novelties that make us human may have been introduced during evolution, based on findings in the embryonic cerebral cortex in different mammalian species. The data on the differences in gene expression, new molecular pathways and novel cellular interactions that have led to these evolutionary advances may also provide insight into the pathogenesis and therapies for human-specific neuropsychiatric disorders.

                Author and article information

                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                18 June 2019
                30 May 2019
                30 May 2019
                : 116
                : 25
                : 12494-12499
                aBrain Science Institute, Korea Institute of Science and Technology , 02792 Seoul, Korea;
                bCollege of Pharmacy, Chung-ang University , 06974 Seoul, Korea;
                cDivision of Bio-Medical Science and Technology, Korea Institute of Science and Technology , 02792 Seoul, Korea;
                dDepartment of Biomedical Engineering, Hanyang University , 04763 Seoul, Korea;
                eDepartment of Anatomy, College of Medicine, Catholic University , 06591 Seoul, Korea
                Author notes
                2To whom correspondence may be addressed. Email: utoh@ .

                Edited by Lily Y. Jan, University of California, San Francisco, CA, and approved May 8, 2019 (received for review February 8, 2019)

                Author contributions: U.O. designed research; G.-S.H., S.H.L., B.L., J.H.C., S.-J.O., Y.J., E.M.H., J.J., and I.-B.K. performed research; H.K. contributed new reagents/analytic tools; G.-S.H., S.H.L., and U.O. analyzed data; and G.-S.H. and U.O. wrote the paper.

                1G.-S.H. and S.H.L. contributed equally to this work.

                Copyright © 2019 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

                Page count
                Pages: 6
                Funded by: National Research Foundation of Korea (NRF) 501100003725
                Award ID: 2011-0018358
                Award Recipient : Uhtaek Oh
                Biological Sciences


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