{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:54:25Z","timestamp":1791093265889,"version":"4.1.0"},"reference-count":49,"publisher":"The Company of Biologists","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,1,15]]},"abstract":"<jats:p>During embryonic development, the rostral neuroectoderm is regionalized into broad areas that are subsequently subdivided into progenitor compartments with specialized identity and fate. These events are controlled by signals emitted by organizing centers and interpreted by target progenitors, which activate superimposing waves of intrinsic factors restricting their identity and fate. The transcription factor Otx2 plays a crucial role in mesencephalic development by positioning the midbrain-hindbrain boundary (MHB) and its organizing activity. Here, we investigated whether Otx2 is cell-autonomously required to control identity and fate of dorsal mesencephalic progenitors. With this aim, we have inactivated Otx2 in the Pax7+ dorsal mesencephalic domain, previously named m1, without affecting MHB integrity. We found that the Pax7+ m1 domain can be further subdivided into a dorsal Zic1+ m1a and a ventral Zic1- m1b sub-domain. Loss of Otx2 in the m1a (Pax7+ Zic1+) sub-domain impairs the identity and fate of progenitors, which undergo a full switch into a coordinated cerebellum differentiation program. By contrast, in the m1b sub-domain (Pax7+ Zic1-) Otx2 is prevalently required for post-mitotic transition of mesencephalic GABAergic precursors. Moreover, genetic cell fate, BrdU cell labeling and Otx2 conditional inactivation experiments indicate that in Otx2 mutants all ectopic cerebellar cell types, including external granule cell layer (EGL) precursors, originate from the m1a progenitor sub-domain and that reprogramming of mesencephalic precursors into EGL or cerebellar GABAergic progenitors depends on temporal sensitivity to Otx2 ablation. Together, these findings indicate that Otx2 intrinsically controls different aspects of dorsal mesencephalic neurogenesis. In this context, Otx2 is cell-autonomously required in the m1a sub-domain to suppress cerebellar fate and promote mesencephalic differentiation independently of the MHB organizing activity.<\/jats:p>","DOI":"10.1242\/dev.102954","type":"journal-article","created":{"date-parts":[[2013,12,12]],"date-time":"2013-12-12T01:15:39Z","timestamp":1386810939000},"page":"377-388","source":"Crossref","is-referenced-by-count":27,"title":["Otx2 cell-autonomously determines dorsal mesencephalon versus cerebellum fate independently of isthmic organizing activity"],"prefix":"10.1242","volume":"141","author":[{"given":"Luca G.","family":"Di Giovannantonio","sequence":"first","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cAdriano Buzzati-Traverso\u201d, CNR, Via P. Castellino 111, 80131 Naples, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Di Salvio","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cAdriano Buzzati-Traverso\u201d, CNR, Via P. Castellino 111, 80131 Naples, Italy."},{"name":"CEINGE Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Omodei","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cAdriano Buzzati-Traverso\u201d, CNR, Via P. Castellino 111, 80131 Naples, Italy."},{"name":"CEINGE Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilima","family":"Prakash","sequence":"additional","affiliation":[{"name":"Institute of Developmental Genetics, Helmholtz Zentrum M\u00fcnchen, Deutsches Forschungszentrum f\u00fcr Gesundheit und Umwelt (GmbH), and Technische Universit\u00e4t M\u00fcnchen-Weihenstephan, Lehrstuhl f\u00fcr Entwicklungsgenetik, Ingolst\u00e4dter Landstrasse 1, D-85764 Neuherberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Wurst","sequence":"additional","affiliation":[{"name":"Institute of Developmental Genetics, Helmholtz Zentrum M\u00fcnchen, Deutsches Forschungszentrum f\u00fcr Gesundheit und Umwelt (GmbH), and Technische Universit\u00e4t M\u00fcnchen-Weihenstephan, Lehrstuhl f\u00fcr Entwicklungsgenetik, Ingolst\u00e4dter Landstrasse 1, D-85764 Neuherberg, Germany."},{"name":"Deutsches Zentrum f\u00fcr Neurodegenerative Erkrankungen (DZNE) Standort M\u00fcnchen, Schillerstrasse 44, D-80336 M\u00fcnchen, Germany."},{"name":"Max-Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804 M\u00fcnchen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Pierani","sequence":"additional","affiliation":[{"name":"Institut Jacques Monod, CNRS UMR 7592, Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, 75205 Paris Cedex, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Acampora","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cAdriano Buzzati-Traverso\u201d, CNR, Via P. Castellino 111, 80131 Naples, Italy."},{"name":"IRCCS Neuromed, 86077 Pozzilli (IS), Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Simeone","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cAdriano Buzzati-Traverso\u201d, CNR, Via P. Castellino 111, 80131 Naples, Italy."},{"name":"IRCCS Neuromed, 86077 Pozzilli (IS), Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042607481459500_R1","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1242\/dev.124.18.3639","article-title":"Genetic control of brain morphogenesis through Otx gene dosage requirement","volume":"124","author":"Acampora","year":"1997","journal-title":"Development"},{"key":"2021042607481459500_R2","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1242\/dev.037770","article-title":"Meis2 competes with the Groucho co-repressor Tle4 for binding to Otx2 and specifies tectal fate without induction of a secondary midbrain-hindbrain boundary organizer","volume":"136","author":"Agoston","year":"2009","journal-title":"Development"},{"key":"2021042607481459500_R3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1471-213X-12-10","article-title":"Genetic and physical interaction of Meis2, Pax3 and Pax7 during dorsal midbrain development","volume":"12","author":"Agoston","year":"2012","journal-title":"BMC Dev. Biol."},{"key":"2021042607481459500_R4","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1002\/neu.480241007","article-title":"Fate and potentialities of the avian mesencephalic\/metencephalic neuroepithelium","volume":"24","author":"Alvarado-Mallart","year":"1993","journal-title":"J. Neurobiol."},{"key":"2021042607481459500_R5","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.cell.2005.10.037","article-title":"Identification of intrinsic determinants of midbrain dopamine neurons","volume":"124","author":"Andersson","year":"2006","journal-title":"Cell"},{"key":"2021042607481459500_R6","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/nn1511","article-title":"Multiple origins of Cajal-Retzius cells at the borders of the developing pallium","volume":"8","author":"Bielle","year":"2005","journal-title":"Nat. Neurosci."},{"key":"2021042607481459500_R7","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0959-4388(00)00172-0","article-title":"Specification of neuronal fates in the ventral neural tube","volume":"11","author":"Briscoe","year":"2001","journal-title":"Curr. Opin. Neurobiol."},{"key":"2021042607481459500_R8","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/43670","article-title":"The caudal limit of Otx2 expression positions the isthmic organizer","volume":"401","author":"Broccoli","year":"1999","journal-title":"Nature"},{"key":"2021042607481459500_R9","doi-asserted-by":"crossref","first-page":"e19367","DOI":"10.1371\/journal.pone.0019367","article-title":"Dbx1-expressing cells are necessary for the survival of the mammalian anterior neural and craniofacial structures","volume":"6","author":"Causeret","year":"2011","journal-title":"PLoS ONE"},{"key":"2021042607481459500_R10","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/380066a0","article-title":"Midbrain development induced by FGF8 in the chick embryo","volume":"380","author":"Crossley","year":"1996","journal-title":"Nature"},{"key":"2021042607481459500_R11","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.ydbio.2012.10.022","article-title":"Otx2 selectively controls the neurogenesis of specific neuronal subtypes of the ventral tegmental area and compensates En1-dependent neuronal loss and MPTP vulnerability","volume":"373","author":"Di Giovannantonio","year":"2013","journal-title":"Dev. Biol."},{"key":"2021042607481459500_R12","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1038\/nn.2661","article-title":"Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP","volume":"13","author":"Di Salvio","year":"2010","journal-title":"Nat. Neurosci."},{"key":"2021042607481459500_R13","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1242\/dev.02352","article-title":"Differentiation of cerebellar cell identities in absence of Fgf signalling in zebrafish Otx morphants","volume":"133","author":"Foucher","year":"2006","journal-title":"Development"},{"key":"2021042607481459500_R14","doi-asserted-by":"crossref","first-page":"5725","DOI":"10.1523\/JNEUROSCI.14-10-05725.1994","article-title":"Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum","volume":"14","author":"Frantz","year":"1994","journal-title":"J. Neurosci."},{"key":"2021042607481459500_R15","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.neuroscience.2008.12.016","article-title":"Basic molecular fingerprinting of immature cerebellar cortical inhibitory interneurons and their precursors","volume":"159","author":"Glassmann","year":"2009","journal-title":"Neuroscience"},{"key":"2021042607481459500_R16","doi-asserted-by":"crossref","first-page":"3847","DOI":"10.1242\/dev.02557","article-title":"Megane\/Heslike is required for normal GABAergic differentiation in the mouse superior colliculus","volume":"133","author":"Guimera","year":"2006","journal-title":"Development"},{"key":"2021042607481459500_R17","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S0959-4388(97)80118-3","article-title":"Genes involved in cerebellar cell specification and differentiation","volume":"7","author":"Hatten","year":"1997","journal-title":"Curr. Opin. Neurobiol."},{"key":"2021042607481459500_R18","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1128\/MCB.00811-06","article-title":"Gbx2 and Otx2 interact with the WD40 domain of Groucho\/Tle corepressors","volume":"27","author":"Heimbucher","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"2021042607481459500_R19","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/35049541","article-title":"Neuronal specification in the spinal cord: inductive signals and transcriptional codes","volume":"1","author":"Jessell","year":"2000","journal-title":"Nat. Rev. Genet."},{"key":"2021042607481459500_R20","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1242\/dev.090860","article-title":"The transcription factor Otx2 regulates choroid plexus development and function","volume":"140","author":"Johansson","year":"2013","journal-title":"Development"},{"key":"2021042607481459500_R21","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1242\/dev.029900","article-title":"Gata2 is a tissue-specific post-mitotic selector gene for midbrain GABAergic neurons","volume":"136","author":"Kala","year":"2009","journal-title":"Development"},{"key":"2021042607481459500_R22","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1146\/annurev.neuro.24.1.869","article-title":"Early anterior\/posterior patterning of the midbrain and cerebellum","volume":"24","author":"Liu","year":"2001","journal-title":"Annu. Rev. Neurosci."},{"key":"2021042607481459500_R23","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1242\/dev.128.2.181","article-title":"EN and GBX2 play essential roles downstream of FGF8 in patterning the mouse mid\/hindbrain region","volume":"128","author":"Liu","year":"2001","journal-title":"Development"},{"key":"2021042607481459500_R24","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1126\/science.274.5290.1109","article-title":"Patterning the vertebrate neuraxis","volume":"274","author":"Lumsden","year":"1996","journal-title":"Science"},{"key":"2021042607481459500_R25","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/(SICI)1097-4695(19991105)41:2<281::AID-NEU10>3.0.CO;2-5","article-title":"Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum","volume":"41","author":"Maricich","year":"1999","journal-title":"J. Neurobiol."},{"key":"2021042607481459500_R26","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0896-6273(91)90237-T","article-title":"Induction of a mesencephalic phenotype in the 2-day-old chick prosencephalon is preceded by the early expression of the homeobox gene en","volume":"6","author":"Martinez","year":"1991","journal-title":"Neuron"},{"key":"2021042607481459500_R27","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1242\/dev.126.6.1189","article-title":"FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression","volume":"126","author":"Martinez","year":"1999","journal-title":"Development"},{"key":"2021042607481459500_R28","doi-asserted-by":"crossref","first-page":"4789","DOI":"10.1242\/dev.128.23.4789","article-title":"Regionalisation of anterior neuroectoderm and its competence in responding to forebrain and midbrain inducing activities depend on mutual antagonism between OTX2 and GBX2","volume":"128","author":"Martinez-Barbera","year":"2001","journal-title":"Development"},{"key":"2021042607481459500_R29","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/43664","article-title":"A role for Gbx2 in repression of Otx2 and positioning the mid\/hindbrain organizer","volume":"401","author":"Millet","year":"1999","journal-title":"Nature"},{"key":"2021042607481459500_R30","doi-asserted-by":"crossref","first-page":"12226","DOI":"10.1523\/JNEUROSCI.3493-06.2006","article-title":"Molecular markers of neuronal progenitors in the embryonic cerebellar anlage","volume":"26","author":"Morales","year":"2006","journal-title":"J. Neurosci."},{"key":"2021042607481459500_R31","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0166-2236(00)01676-3","article-title":"Regionalization of the optic tectum: combinations of gene expression that define the tectum","volume":"24","author":"Nakamura","year":"2001","journal-title":"Trends Neurosci."},{"key":"2021042607481459500_R32","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1242\/dev.02870","article-title":"Helt determines GABAergic over glutamatergic neuronal fate by repressing Ngn genes in the developing mesencephalon","volume":"134","author":"Nakatani","year":"2007","journal-title":"Development"},{"key":"2021042607481459500_R33","doi-asserted-by":"crossref","first-page":"3459","DOI":"10.1242\/dev.027003","article-title":"Anterior-posterior graded response to Otx2 controls proliferation and differentiation of dopaminergic progenitors in the ventral mesencephalon","volume":"135","author":"Omodei","year":"2008","journal-title":"Development"},{"key":"2021042607481459500_R34","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1242\/dev.02181","article-title":"A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo","volume":"133","author":"Prakash","year":"2006","journal-title":"Development"},{"key":"2021042607481459500_R35","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1242\/dev.031781","article-title":"Nkx6-1 controls the identity and fate of red nucleus and oculomotor neurons in the mouse midbrain","volume":"136","author":"Prakash","year":"2009","journal-title":"Development"},{"key":"2021042607481459500_R36","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nn1037","article-title":"Otx dose-dependent integrated control of antero-posterior and dorso-ventral patterning of midbrain","volume":"6","author":"Puelles","year":"2003","journal-title":"Nat. Neurosci."},{"key":"2021042607481459500_R37","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1242\/dev.01107","article-title":"Otx2 regulates the extent, identity and fate of neuronal progenitor domains in the ventral midbrain","volume":"131","author":"Puelles","year":"2004","journal-title":"Development"},{"key":"2021042607481459500_R38","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0959-4388(00)00171-9","article-title":"The midbrain - hindbrain boundary organizer","volume":"11","author":"Rhinn","year":"2001","journal-title":"Curr. Opin. Neurobiol."},{"key":"2021042607481459500_R39","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1146\/annurev.neuro.21.1.445","article-title":"Regionalization of the prosencephalic neural plate","volume":"21","author":"Rubenstein","year":"1998","journal-title":"Annu. Rev. Neurosci."},{"key":"2021042607481459500_R40","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1242\/dev.128.13.2461","article-title":"Inductive signal and tissue responsiveness defining the tectum and the cerebellum","volume":"128","author":"Sato","year":"2001","journal-title":"Development"},{"key":"2021042607481459500_R41","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1146\/annurev.cellbio.23.090506.123237","article-title":"Morphology, molecular codes, and circuitry produce the three-dimensional complexity of the cerebellum","volume":"23","author":"Sillitoe","year":"2007","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"2021042607481459500_R42","first-page":"69","article-title":"Detection of mRNA in tissue sections with radiolabelled riboprobes","volume-title":"In Situ Hybridization. A Practical Approach","author":"Simeone","year":"1999","edition":"2nd edn"},{"key":"2021042607481459500_R43","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0168-9525(00)02000-X","article-title":"Positioning the isthmic organizer where Otx2 and Gbx2meet","volume":"16","author":"Simeone","year":"2000","journal-title":"Trends Genet."},{"key":"2021042607481459500_R44","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S0959-437X(02)00318-0","article-title":"The Otx family","volume":"12","author":"Simeone","year":"2002","journal-title":"Curr. Opin. Genet. Dev."},{"key":"2021042607481459500_R45","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrn2039","article-title":"How to make a mesodiencephalic dopaminergic neuron","volume":"8","author":"Smidt","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"2021042607481459500_R46","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.brainres.2006.04.127","article-title":"Stem cell marker expression in the Bergmann glia population of the adult mouse brain","volume":"1099","author":"Sottile","year":"2006","journal-title":"Brain Res."},{"key":"2021042607481459500_R47","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1111\/j.1460-9568.2006.04915.x","article-title":"Postnatal development of the murine cerebellar cortex: formation and early dispersal of basket, stellate and Golgi neurons","volume":"24","author":"Weisheit","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"2021042607481459500_R48","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/35053516","article-title":"Neural plate patterning: upstream and downstream of the isthmic organizer","volume":"2","author":"Wurst","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"2021042607481459500_R49","doi-asserted-by":"crossref","first-page":"13182","DOI":"10.1073\/pnas.0705464104","article-title":"LIM-homeodomain proteins Lhx1 and Lhx5, and their cofactor Ldb1, control Purkinje cell differentiation in the developing cerebellum","volume":"104","author":"Zhao","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/141\/2\/377\/1322672\/377.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/141\/2\/377\/1322672\/377.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T12:10:26Z","timestamp":1619439026000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/141\/2\/377\/46428\/Otx2-cell-autonomously-determines-dorsal"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,15]]},"references-count":49,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2014,1,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.102954","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2014,1,15]]}}}