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A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding

The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, results mai...

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Autores principales: Wang, Lei, Park, Jun Young, Liu, Fengming, Olesen, Kris M., Hou, Shirui, Peng, Jamy C., Infield, Jordan, Levesque, Anna C., Wang, Yong-Dong, Jin, Hongjian, Fan, Yiping, Connelly, Patrick J., Pruett-Miller, Shondra M., Hu, Miaofen G., Hinds, Philip W., Han, Young-Goo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499540/
https://www.ncbi.nlm.nih.gov/pubmed/36095192
http://dx.doi.org/10.1073/pnas.2206147119
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author Wang, Lei
Park, Jun Young
Liu, Fengming
Olesen, Kris M.
Hou, Shirui
Peng, Jamy C.
Infield, Jordan
Levesque, Anna C.
Wang, Yong-Dong
Jin, Hongjian
Fan, Yiping
Connelly, Patrick J.
Pruett-Miller, Shondra M.
Hu, Miaofen G.
Hinds, Philip W.
Han, Young-Goo
author_facet Wang, Lei
Park, Jun Young
Liu, Fengming
Olesen, Kris M.
Hou, Shirui
Peng, Jamy C.
Infield, Jordan
Levesque, Anna C.
Wang, Yong-Dong
Jin, Hongjian
Fan, Yiping
Connelly, Patrick J.
Pruett-Miller, Shondra M.
Hu, Miaofen G.
Hinds, Philip W.
Han, Young-Goo
author_sort Wang, Lei
collection PubMed
description The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, results mainly from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lissencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion, that oRGs are necessary for neocortical folding, and that defects in oRG expansion may cause primary microcephaly.
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spelling pubmed-94995402023-03-12 A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding Wang, Lei Park, Jun Young Liu, Fengming Olesen, Kris M. Hou, Shirui Peng, Jamy C. Infield, Jordan Levesque, Anna C. Wang, Yong-Dong Jin, Hongjian Fan, Yiping Connelly, Patrick J. Pruett-Miller, Shondra M. Hu, Miaofen G. Hinds, Philip W. Han, Young-Goo Proc Natl Acad Sci U S A Biological Sciences The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, results mainly from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lissencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion, that oRGs are necessary for neocortical folding, and that defects in oRG expansion may cause primary microcephaly. National Academy of Sciences 2022-09-12 2022-09-20 /pmc/articles/PMC9499540/ /pubmed/36095192 http://dx.doi.org/10.1073/pnas.2206147119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Wang, Lei
Park, Jun Young
Liu, Fengming
Olesen, Kris M.
Hou, Shirui
Peng, Jamy C.
Infield, Jordan
Levesque, Anna C.
Wang, Yong-Dong
Jin, Hongjian
Fan, Yiping
Connelly, Patrick J.
Pruett-Miller, Shondra M.
Hu, Miaofen G.
Hinds, Philip W.
Han, Young-Goo
A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding
title A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding
title_full A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding
title_fullStr A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding
title_full_unstemmed A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding
title_short A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding
title_sort kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499540/
https://www.ncbi.nlm.nih.gov/pubmed/36095192
http://dx.doi.org/10.1073/pnas.2206147119
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