{"PubmedArticle":{"MedlineCitation":{"@attributes":{"Status":"MEDLINE","Owner":"NLM","IndexingMethod":"Manual"},"PMID":{"@attributes":{"Version":"1"},"@text":"23334497"},"DateCompleted":{"Year":"2013","Month":"03","Day":"29"},"DateRevised":{"Year":"2021","Month":"10","Day":"21"},"Article":{"@attributes":{"PubModel":"Print-Electronic"},"Journal":{"ISSN":{"@attributes":{"IssnType":"Electronic"},"@text":"1476-4679"},"JournalIssue":{"@attributes":{"CitedMedium":"Internet"},"Volume":"15","Issue":"2","PubDate":{"Year":"2013","Month":"Feb"}},"Title":"Nature cell biology","ISOAbbreviation":"Nat Cell Biol"},"ArticleTitle":"Direct lineage reprogramming of post-mitotic callosal neurons into corticofugal neurons in vivo.","Pagination":{"StartPage":"214","EndPage":"221","MedlinePgn":"214-21"},"ELocationID":[{"@attributes":{"EIdType":"doi","ValidYN":"Y"},"@text":"10.1038\/ncb2660"}],"Abstract":{"AbstractText":["Once programmed to acquire a specific identity and function, cells rarely change in vivo. Neurons of the mammalian central nervous system (CNS) in particular are a classic example of a stable, terminally differentiated cell type. With the exception of the adult neurogenic niches, where a limited set of neuronal subtypes continue to be generated throughout life, CNS neurons are born only during embryonic and early postnatal development. Once generated, neurons become permanently post-mitotic and do not change their identity for the lifespan of the organism. Here, we have investigated whether excitatory neurons of the neocortex can be instructed to directly reprogram their identity post-mitotically from one subtype into another, in vivo. We show that embryonic and early postnatal callosal projection neurons of layer II\/III can be post-mitotically lineage reprogrammed into layer-V\/VI corticofugal projection neurons following expression of the transcription factor encoded by Fezf2. Reprogrammed callosal neurons acquire molecular properties of corticofugal projection neurons and change their axonal connectivity from interhemispheric, intracortical projections to corticofugal projections directed below the cortex. The data indicate that during a window of post-mitotic development neurons can change their identity, acquiring critical features of alternative neuronal lineages."]},"AuthorList":{"@attributes":{"CompleteYN":"Y"},"Author":[{"@attributes":{"ValidYN":"Y"},"LastName":"Rouaux","ForeName":"Caroline","Initials":"C","AffiliationInfo":[{"Affiliation":"Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Arlotta","ForeName":"Paola","Initials":"P"}]},"Language":["eng"],"GrantList":{"@attributes":{"CompleteYN":"Y"},"Grant":[{"GrantID":"R01 NS062849","Acronym":"NS","Agency":"NINDS NIH HHS","Country":"United States"},{"GrantID":"R01 NS073124","Acronym":"NS","Agency":"NINDS NIH HHS","Country":"United States"},{"GrantID":"NS062849","Acronym":"NS","Agency":"NINDS NIH HHS","Country":"United States"}]},"PublicationTypeList":{"PublicationType":[{"@attributes":{"UI":"D016428"},"@text":"Journal Article"},{"@attributes":{"UI":"D052061"},"@text":"Research Support, N.I.H., Extramural"},{"@attributes":{"UI":"D013485"},"@text":"Research Support, Non-U.S. Gov't"}]},"ArticleDate":[{"@attributes":{"DateType":"Electronic"},"Year":"2013","Month":"01","Day":"20"}]},"MedlineJournalInfo":{"Country":"England","MedlineTA":"Nat Cell Biol","NlmUniqueID":"100890575","ISSNLinking":"1465-7392"},"ChemicalList":{"Chemical":[{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D015415"},"@text":"Biomarkers"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D004268"},"@text":"DNA-Binding Proteins"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D009419"},"@text":"Nerve Tissue Proteins"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"C412364"},"@text":"Zfp312 protein, mouse"}}]},"CitationSubset":["IM"],"MeshHeadingList":{"MeshHeading":[{"DescriptorName":{"@attributes":{"UI":"D000818","MajorTopicYN":"N"},"@text":"Animals"}},{"DescriptorName":{"@attributes":{"UI":"D000831","MajorTopicYN":"N"},"@text":"Animals, Newborn"}},{"DescriptorName":{"@attributes":{"UI":"D001369","MajorTopicYN":"N"},"@text":"Axons"},"QualifierName":[{"@attributes":{"UI":"Q000502","MajorTopicYN":"N"},"@text":"physiology"}]},{"DescriptorName":{"@attributes":{"UI":"D015415","MajorTopicYN":"N"},"@text":"Biomarkers"},"QualifierName":[{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"}]},{"DescriptorName":{"@attributes":{"UI":"D019070","MajorTopicYN":"Y"},"@text":"Cell Lineage"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D054338","MajorTopicYN":"Y"},"@text":"Cell Transdifferentiation"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D065150","MajorTopicYN":"Y"},"@text":"Cellular Reprogramming"}},{"DescriptorName":{"@attributes":{"UI":"D003337","MajorTopicYN":"N"},"@text":"Corpus Callosum"},"QualifierName":[{"@attributes":{"UI":"Q000196","MajorTopicYN":"N"},"@text":"embryology"},{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"},{"@attributes":{"UI":"Q000502","MajorTopicYN":"Y"},"@text":"physiology"}]},{"DescriptorName":{"@attributes":{"UI":"D004268","MajorTopicYN":"N"},"@text":"DNA-Binding Proteins"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"},{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"}]},{"DescriptorName":{"@attributes":{"UI":"D018274","MajorTopicYN":"N"},"@text":"Electroporation"}},{"DescriptorName":{"@attributes":{"UI":"D018507","MajorTopicYN":"N"},"@text":"Gene Expression Regulation, Developmental"}},{"DescriptorName":{"@attributes":{"UI":"D053263","MajorTopicYN":"N"},"@text":"Gene Regulatory Networks"}},{"DescriptorName":{"@attributes":{"UI":"D018014","MajorTopicYN":"N"},"@text":"Gene Transfer Techniques"}},{"DescriptorName":{"@attributes":{"UI":"D005865","MajorTopicYN":"N"},"@text":"Gestational Age"}},{"DescriptorName":{"@attributes":{"UI":"D051379","MajorTopicYN":"N"},"@text":"Mice"}},{"DescriptorName":{"@attributes":{"UI":"D008938","MajorTopicYN":"Y"},"@text":"Mitosis"}},{"DescriptorName":{"@attributes":{"UI":"D019579","MajorTopicYN":"N"},"@text":"Neocortex"},"QualifierName":[{"@attributes":{"UI":"Q000196","MajorTopicYN":"N"},"@text":"embryology"},{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"},{"@attributes":{"UI":"Q000502","MajorTopicYN":"Y"},"@text":"physiology"}]},{"DescriptorName":{"@attributes":{"UI":"D009419","MajorTopicYN":"N"},"@text":"Nerve Tissue Proteins"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"},{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"}]},{"DescriptorName":{"@attributes":{"UI":"D009434","MajorTopicYN":"N"},"@text":"Neural Pathways"},"QualifierName":[{"@attributes":{"UI":"Q000502","MajorTopicYN":"N"},"@text":"physiology"}]},{"DescriptorName":{"@attributes":{"UI":"D009474","MajorTopicYN":"N"},"@text":"Neurons"},"QualifierName":[{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"},{"@attributes":{"UI":"Q000502","MajorTopicYN":"Y"},"@text":"physiology"}]}]}},"PubmedData":{"History":{"PubMedPubDate":[{"@attributes":{"PubStatus":"received"},"Year":"2012","Month":"10","Day":"19"},{"@attributes":{"PubStatus":"accepted"},"Year":"2012","Month":"11","Day":"26"},{"@attributes":{"PubStatus":"entrez"},"Year":"2013","Month":"1","Day":"22","Hour":"6","Minute":"0"},{"@attributes":{"PubStatus":"pubmed"},"Year":"2013","Month":"1","Day":"22","Hour":"6","Minute":"0"},{"@attributes":{"PubStatus":"medline"},"Year":"2013","Month":"3","Day":"30","Hour":"6","Minute":"0"},{"@attributes":{"PubStatus":"pmc-release"},"Year":"2014","Month":"8","Day":"1"}]},"PublicationStatus":"ppublish","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"23334497"},{"@attributes":{"IdType":"mid"},"@text":"NIHMS586092"},{"@attributes":{"IdType":"pmc"},"@text":"PMC4118591"},{"@attributes":{"IdType":"doi"},"@text":"10.1038\/ncb2660"},{"@attributes":{"IdType":"pii"},"@text":"ncb2660"}]},"ReferenceList":[{"Reference":[{"Citation":"Waddington CH. The strategy of the genes; a discussion of some aspects of theoretical biology. Allen &amp; Unwin; 1957."},{"Citation":"Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci. 2005;28:223\u2013250.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"16022595"}]}},{"Citation":"Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132:645\u2013660.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"18295581"}]}},{"Citation":"Selvaraj V, Plane JM, Williams AJ, Deng W. Switching cell fate: the remarkable rise of induced pluripotent stem cells and lineage reprogramming technologies. Trends Biotechnol. 2010;28:214\u2013223.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC2843790"},{"@attributes":{"IdType":"pubmed"},"@text":"20149468"}]}},{"Citation":"Vierbuchen T, Wernig M. Direct lineage conversions: unnatural but useful? Nat Biotechnol. 2011;29:892\u2013907.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC3222779"},{"@attributes":{"IdType":"pubmed"},"@text":"21997635"}]}},{"Citation":"Zhou Q, Melton DA. Extreme makeover: converting one cell into another. Cell Stem Cell. 2008;3:382\u2013388.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"18940730"}]}},{"Citation":"Eggan K, et al. Mice cloned from olfactory sensory neurons. Nature. 2004;428:44\u201349.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"14990966"}]}},{"Citation":"Li J, Ishii T, Feinstein P, Mombaerts P. Odorant receptor gene choice is reset by nuclear transfer from mouse olfactory sensory neurons. Nature. 2004;428:393\u2013399.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"15042081"}]}},{"Citation":"De Marco Garcia NV, Jessell TM. Early motor neuron pool identity and muscle nerve trajectory defined by postmitotic restrictions in Nkx6.1 activity. Neuron. 2008;57:217\u2013231.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC2276619"},{"@attributes":{"IdType":"pubmed"},"@text":"18215620"}]}},{"Citation":"Sharma K, Leonard AE, Lettieri K, Pfaff SL. Genetic and epigenetic mechanisms contribute to motor neuron pathfinding. Nature. 2000;406:515\u2013519. doi: 10.1038\/35020078.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"doi"},"@text":"10.1038\/35020078"},{"@attributes":{"IdType":"pubmed"},"@text":"10952312"}]}},{"Citation":"Thaler JP, et al. A postmitotic role for Isl-class LIM homeodomain proteins in the assignment of visceral spinal motor neuron identity. Neuron. 2004;41:337\u2013350.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"14766174"}]}},{"Citation":"Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD. Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci. 2007;8:427\u2013437.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"17514196"}]}},{"Citation":"Bayer SA, Altman J. Neocortical Development. Raven Press; 1991."},{"Citation":"Arlotta P, et al. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron. 2005;45:207\u2013221.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"15664173"}]}},{"Citation":"Chen B, Schaevitz LR, McConnell SK. Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex. Proc Natl Acad Sci U S A. 2005;102:17184\u201317189.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC1282569"},{"@attributes":{"IdType":"pubmed"},"@text":"16284245"}]}},{"Citation":"Chen JG, Rasin MR, Kwan KY, Sestan N. Zfp312 is required for subcortical axonal projections and dendritic morphology of deep-layer pyramidal neurons of the cerebral cortex. Proc Natl Acad Sci U S A. 2005;102:17792\u201317797.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC1308928"},{"@attributes":{"IdType":"pubmed"},"@text":"16314561"}]}},{"Citation":"Molyneaux BJ, Arlotta P, Hirata T, Hibi M, Macklis JD. Fezl is required for the birth and specification of corticospinal motor neurons. Neuron. 2005;47:817\u2013831.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"16157277"}]}},{"Citation":"Rouaux C, Arlotta P. Fezf2 directs the differentiation of corticofugal neurons from striatal progenitors in vivo. Nat Neurosci. 2010;13:1345\u20131347.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC4207442"},{"@attributes":{"IdType":"pubmed"},"@text":"20953195"}]}},{"Citation":"Wang X, Qiu R, Tsark W, Lu Q. Rapid promoter analysis in developing mouse brain and genetic labeling of young neurons by doublecortin-DsRed-express. J Neurosci Res. 2007;85:3567\u20133573.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"17671991"}]}},{"Citation":"Delalle I, Bhide PG, Caviness VS, Jr, Tsai LH. Temporal and spatial patterns of expression of p35, a regulatory subunit of cyclin-dependent kinase 5, in the nervous system of the mouse. J Neurocytol. 1997;26:283\u2013296.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"9192293"}]}},{"Citation":"Tsai LH, Delalle I, Caviness VS, Jr, Chae T, Harlow E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature. 1994;371:419\u2013423.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"8090221"}]}},{"Citation":"Yoneshima H, et al. Er81 is expressed in a subpopulation of layer 5 neurons in rodent and primate neocortices. Neuroscience. 2006;137:401\u2013412.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"16289830"}]}},{"Citation":"Molyneaux BJ, et al. Novel subtype-specific genes identify distinct subpopulations of callosal projection neurons. J Neurosci. 2009;29:12343\u201312354.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC2776075"},{"@attributes":{"IdType":"pubmed"},"@text":"19793993"}]}},{"Citation":"Fishell G, Hanashima C. Pyramidal neurons grow up and change their mind. Neuron. 2008;57:333\u2013338.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"18255026"}]}},{"Citation":"Matsuda T, Cepko CL. Controlled expression of transgenes introduced by in vivo electroporation. Proc Natl Acad Sci U S A. 2007;104:1027\u20131032.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC1764220"},{"@attributes":{"IdType":"pubmed"},"@text":"17209010"}]}},{"Citation":"Huangfu D, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol. 2008;26:1269\u20131275.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"18849973"}]}},{"Citation":"Fame RM, MacDonald JL, Macklis JD. Development, specification, and diversity of callosal projection neurons. Trends Neurosci. 2011;34:41\u201350.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC3053014"},{"@attributes":{"IdType":"pubmed"},"@text":"21129791"}]}},{"Citation":"Ozaki HS, Wahlsten D. Timing and origin of the first cortical axons to project through the corpus callosum and the subsequent emergence of callosal projection cells in mouse. J Comp Neurol. 1998;400:197\u2013206.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"9766399"}]}},{"Citation":"Francis F, et al. Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron. 1999;23:247\u2013256.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"10399932"}]}},{"Citation":"Gleeson JG, Lin PT, Flanagan LA, Walsh CA. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron. 1999;23:257\u2013271.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"10399933"}]}},{"Citation":"Matsuo N, Kawamoto S, Matsubara K, Okubo K. Cloning and developmental expression of the murine homolog of doublecortin. Biochem Biophys Res Commun. 1998;252:571\u2013 576.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"9837748"}]}},{"Citation":"Rouaux C, Bhai S, Arlotta P. Programming and reprogramming neuronal subtypes in the central nervous system. Dev Neurobiol. 2012","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC4123849"},{"@attributes":{"IdType":"pubmed"},"@text":"22378700"}]}},{"Citation":"Berninger B, et al. Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia. J Neurosci. 2007;27:8654\u20138664.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC6672931"},{"@attributes":{"IdType":"pubmed"},"@text":"17687043"}]}},{"Citation":"Heinrich C, et al. Directing Astroglia from the Cerebral Cortex into Subtype Specific Functional Neurons. Plos Biol. 2010;8","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC2872647"},{"@attributes":{"IdType":"pubmed"},"@text":"20502524"}]}},{"Citation":"Heins N, et al. Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci. 2002;5:308\u2013315.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"11896398"}]}},{"Citation":"Karow M, et al. Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell. 2012;11:471\u2013476.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"23040476"}]}},{"Citation":"Cardin JA, et al. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature. 2009;459:663\u2013667.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC3655711"},{"@attributes":{"IdType":"pubmed"},"@text":"19396156"}]}},{"Citation":"Saito T, Nakatsuji N. Efficient gene transfer into the embryonic mouse brain using in vivo electroporation. Dev Biol. 2001;240:237\u2013246.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"11784059"}]}},{"Citation":"Lodato S, et al. Excitatory projection neuron subtypes control the distribution of local inhibitory interneurons in the cerebral cortex. Neuron. 2011;69:763\u2013779.","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pmc"},"@text":"PMC3061282"},{"@attributes":{"IdType":"pubmed"},"@text":"21338885"}]}}]}]}}}