[{"corr_author":"1","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","image":"/images/cc_by_nc.png","short":"CC BY-NC (4.0)"},"doi":"10.64898/2026.05.01.722191","article_processing_charge":"No","date_created":"2026-06-09T08:08:53Z","status":"public","abstract":[{"text":"The cerebral cortex consists of immense numbers of neuronal and glial cell-types derived from radial glial progenitor (RGP) cells. How RGPs generate appropriate quantities of distinct cortical cell-types to safeguard a brain of correct size, is not well understood. However, genetic aberration in human, including mutations in PTEN, lead to cortical malformation such as macrocephaly, albeit with unknown etiology. Here we utilized Mosaic Analysis with Double Markers (MADM)-based clonal analysis and single cell phenotyping to decipher the role of Pten in neurogenic and gliogenic RGP lineage progression during cortical ontogeny. While neurogenic RGP lineage progression and projection neuron production was moderately altered in the absence of Pten, cortical astrocyte production was drastically increased. Through genetic epistasis experiments we show that the loss of Pten uncouples astrocyte generation from essential growth factor signaling hubs, funneling into MAPK. Collectively, our results suggest that Pten regulates RGP lineage progression with distinct sequential functions in cortical projection neurogenesis and astrocyte production to ensure the emergence of a correctly-sized cerebral cortex.","lang":"eng"}],"main_file_link":[{"url":"https://doi.org/10.64898/2026.05.01.722191","open_access":"1"}],"oa":1,"citation":{"chicago":"Miranda, Osvaldo, Ximena Contreras, Florian Pauler, Amarbayasgalan Davaatseren, Nicole Amberg, Carmen Streicher, Ana Villalba Requena, et al. “Pten Orchestrates Neurogenic Radial Glia Lineage Progression and Tunes Neocortical Astrocyte Production.” <i>BioRxiv</i>, n.d. <a href=\"https://doi.org/10.64898/2026.05.01.722191\">https://doi.org/10.64898/2026.05.01.722191</a>.","ista":"Miranda O, Contreras X, Pauler F, Davaatseren A, Amberg N, Streicher C, Villalba Requena A, Heger A-M, Marie C, Hassan BA, Rülicke T, Hippenmeyer S. Pten orchestrates neurogenic radial glia lineage progression and tunes neocortical astrocyte production. bioRxiv, <a href=\"https://doi.org/10.64898/2026.05.01.722191\">10.64898/2026.05.01.722191</a>.","ieee":"O. Miranda <i>et al.</i>, “Pten orchestrates neurogenic radial glia lineage progression and tunes neocortical astrocyte production,” <i>bioRxiv</i>. .","ama":"Miranda O, Contreras X, Pauler F, et al. Pten orchestrates neurogenic radial glia lineage progression and tunes neocortical astrocyte production. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.64898/2026.05.01.722191\">10.64898/2026.05.01.722191</a>","short":"O. Miranda, X. Contreras, F. Pauler, A. Davaatseren, N. Amberg, C. Streicher, A. Villalba Requena, A.-M. Heger, C. Marie, B.A. Hassan, T. Rülicke, S. Hippenmeyer, BioRxiv (n.d.).","apa":"Miranda, O., Contreras, X., Pauler, F., Davaatseren, A., Amberg, N., Streicher, C., … Hippenmeyer, S. (n.d.). Pten orchestrates neurogenic radial glia lineage progression and tunes neocortical astrocyte production. <i>bioRxiv</i>. <a href=\"https://doi.org/10.64898/2026.05.01.722191\">https://doi.org/10.64898/2026.05.01.722191</a>","mla":"Miranda, Osvaldo, et al. “Pten Orchestrates Neurogenic Radial Glia Lineage Progression and Tunes Neocortical Astrocyte Production.” <i>BioRxiv</i>, doi:<a href=\"https://doi.org/10.64898/2026.05.01.722191\">10.64898/2026.05.01.722191</a>."},"date_updated":"2026-06-16T08:57:20Z","month":"05","date_published":"2026-05-05T00:00:00Z","publication":"bioRxiv","OA_place":"repository","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"PreCl"}],"type":"preprint","title":"Pten orchestrates neurogenic radial glia lineage progression and tunes neocortical astrocyte production","language":[{"iso":"eng"}],"acknowledgement":"We thank Kay-Uwe Wagner (Wayne State University) for generously sharing Jak1/2–flox mouse lines; A.\r\nSommer (VBCF GmbH, NGS Unit) for technical support; N. Kim, V. Mick, S. Schnabl, S. Gobeil, and L.\r\nAndersen for technical assistance; all members of the Hippenmeyer lab for discussion and B. Novitch for\r\ncomments on earlier versions of the manuscript. This research was supported by the Scientific Service Units\r\n(SSU) of IST Austria through resources provided by the Imaging and Optics Facility (IOF), Lab Support-\r\n(LSF) and Preclinical Facilities (PCF). O.A.M received support from the Austrian Academy of Sciences\r\nÖAW (DOC 186584), and N.A. from FWF Elise Richter Program (Grant V1041T). This work was also\r\nsupported by IST Austria institutional funds; FWF SFB F78 (Neuro Stem Modulation) to S.H., and the\r\nEuropean Research Council (ERC) under the European Union’s Horizon 2020 research and innovation\r\nprogramme (grant agreement No 725780 LinPro) to S.H.","OA_type":"green","department":[{"_id":"SiHi"},{"_id":"PreCl"},{"_id":"GradSch"}],"ddc":["570"],"year":"2026","_id":"21963","day":"05","author":[{"id":"862A3C56-A8BF-11E9-B4FA-D9E3E5697425","full_name":"Miranda, Osvaldo","orcid":"0000-0001-6618-6889","first_name":"Osvaldo","last_name":"Miranda"},{"id":"475990FE-F248-11E8-B48F-1D18A9856A87","full_name":"Contreras, Ximena","first_name":"Ximena","last_name":"Contreras"},{"first_name":"Florian","last_name":"Pauler","orcid":"0000-0002-7462-0048","full_name":"Pauler, Florian","id":"48EA0138-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Davaatseren, Amarbayasgalan","id":"70ADC922-B424-11E9-99E3-BA18E6697425","first_name":"Amarbayasgalan","last_name":"Davaatseren"},{"orcid":"0000-0002-3183-8207","full_name":"Amberg, Nicole","id":"4CD6AAC6-F248-11E8-B48F-1D18A9856A87","first_name":"Nicole","last_name":"Amberg"},{"first_name":"Carmen","last_name":"Streicher","full_name":"Streicher, Carmen","id":"36BCB99C-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0002-5615-5277","id":"68cb85a0-39f7-11eb-9559-9aaab4f6a247","full_name":"Villalba Requena, Ana","last_name":"Villalba Requena","first_name":"Ana"},{"first_name":"Anna-Magdalena","last_name":"Heger","full_name":"Heger, Anna-Magdalena","id":"4B76FFD2-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Marie, Corentine","first_name":"Corentine","last_name":"Marie"},{"first_name":"Bassem A.","last_name":"Hassan","full_name":"Hassan, Bassem A."},{"last_name":"Rülicke","first_name":"Thomas","full_name":"Rülicke, Thomas"},{"first_name":"Simon","last_name":"Hippenmeyer","full_name":"Hippenmeyer, Simon","id":"37B36620-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2279-1061"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","has_accepted_license":"1","oa_version":"Preprint","publication_status":"submitted","project":[{"_id":"059F6AB4-7A3F-11EA-A408-12923DDC885E","grant_number":"F7805","name":"Stem Cell Modulation in Neural Development and Regeneration/ P05-Molecular Mechanisms of Neural Stem Cell Lineage Progression"},{"grant_number":"725780","_id":"260018B0-B435-11E9-9278-68D0E5697425","name":"Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development","call_identifier":"H2020"}],"ec_funded":1},{"department":[{"_id":"SiHi"},{"_id":"LoSw"},{"_id":"PreCl"}],"related_material":{"link":[{"relation":"press_release","url":"https://ist.ac.at/en/news/boost-for-mouse-genetic-analysis/","description":"News on IST Homepage"}]},"scopus_import":"1","quality_controlled":"1","isi":1,"day":"22","_id":"9603","year":"2021","ddc":["570"],"article_type":"original","intvolume":"        35","file":[{"relation":"main_file","checksum":"d49520fdcbbb5c2f883bddb67cee5d77","file_size":7653149,"success":1,"date_updated":"2021-06-28T14:06:24Z","file_id":"9613","access_level":"open_access","content_type":"application/pdf","creator":"asandaue","date_created":"2021-06-28T14:06:24Z","file_name":"2021_CellReports_Contreras.pdf"}],"volume":35,"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","has_accepted_license":"1","oa_version":"Published Version","author":[{"id":"475990FE-F248-11E8-B48F-1D18A9856A87","full_name":"Contreras, Ximena","last_name":"Contreras","first_name":"Ximena"},{"last_name":"Amberg","first_name":"Nicole","full_name":"Amberg, Nicole","id":"4CD6AAC6-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-3183-8207"},{"first_name":"Amarbayasgalan","last_name":"Davaatseren","full_name":"Davaatseren, Amarbayasgalan","id":"70ADC922-B424-11E9-99E3-BA18E6697425"},{"first_name":"Andi H","last_name":"Hansen","id":"38853E16-F248-11E8-B48F-1D18A9856A87","full_name":"Hansen, Andi H"},{"last_name":"Sonntag","first_name":"Johanna","full_name":"Sonntag, Johanna","id":"32FE7D7C-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Lill","last_name":"Andersen","full_name":"Andersen, Lill"},{"first_name":"Tina","last_name":"Bernthaler","full_name":"Bernthaler, Tina"},{"last_name":"Streicher","first_name":"Carmen","id":"36BCB99C-F248-11E8-B48F-1D18A9856A87","full_name":"Streicher, Carmen"},{"last_name":"Heger","first_name":"Anna-Magdalena","id":"4B76FFD2-F248-11E8-B48F-1D18A9856A87","full_name":"Heger, Anna-Magdalena"},{"last_name":"Johnson","first_name":"Randy L.","full_name":"Johnson, Randy L."},{"last_name":"Schwarz","first_name":"Lindsay A.","full_name":"Schwarz, Lindsay A."},{"first_name":"Liqun","last_name":"Luo","full_name":"Luo, Liqun"},{"full_name":"Rülicke, Thomas","first_name":"Thomas","last_name":"Rülicke"},{"first_name":"Simon","last_name":"Hippenmeyer","id":"37B36620-F248-11E8-B48F-1D18A9856A87","full_name":"Hippenmeyer, Simon","orcid":"0000-0003-2279-1061"}],"file_date_updated":"2021-06-28T14:06:24Z","ec_funded":1,"publication_status":"published","project":[{"name":"Molecular mechanisms of radial neuronal migration","_id":"2625A13E-B435-11E9-9278-68D0E5697425","grant_number":"24812"},{"name":"Molecular Mechanisms of Cerebral Cortex Development","grant_number":"618444","_id":"25D61E48-B435-11E9-9278-68D0E5697425","call_identifier":"FP7"},{"name":"Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development","grant_number":"725780","_id":"260018B0-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"}],"publication_identifier":{"eissn":["2211-1247"]},"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","image":"/images/cc_by_nc_nd.png","short":"CC BY-NC-ND (4.0)"},"doi":"10.1016/j.celrep.2021.109274","article_processing_charge":"No","external_id":{"isi":["000664463600016"],"pmid":["34161767"]},"date_created":"2021-06-27T22:01:48Z","status":"public","publication":"Cell Reports","date_updated":"2026-04-02T14:04:28Z","article_number":"109274","date_published":"2021-06-22T00:00:00Z","month":"06","abstract":[{"text":"Mosaic analysis with double markers (MADM) offers one approach to visualize and concomitantly manipulate genetically defined cells in mice with single-cell resolution. MADM applications include the analysis of lineage, single-cell morphology and physiology, genomic imprinting phenotypes, and dissection of cell-autonomous gene functions in vivo in health and disease. Yet, MADM can only be applied to <25% of all mouse genes on select chromosomes to date. To overcome this limitation, we generate transgenic mice with knocked-in MADM cassettes near the centromeres of all 19 autosomes and validate their use across organs. With this resource, >96% of the entire mouse genome can now be subjected to single-cell genetic mosaic analysis. Beyond a proof of principle, we apply our MADM library to systematically trace sister chromatid segregation in distinct mitotic cell lineages. We find striking chromosome-specific biases in segregation patterns, reflecting a putative mechanism for the asymmetric segregation of genetic determinants in somatic stem cell division.","lang":"eng"}],"oa":1,"citation":{"apa":"Contreras, X., Amberg, N., Davaatseren, A., Hansen, A. H., Sonntag, J., Andersen, L., … Hippenmeyer, S. (2021). A genome-wide library of MADM mice for single-cell genetic mosaic analysis. <i>Cell Reports</i>. Cell Press. <a href=\"https://doi.org/10.1016/j.celrep.2021.109274\">https://doi.org/10.1016/j.celrep.2021.109274</a>","mla":"Contreras, Ximena, et al. “A Genome-Wide Library of MADM Mice for Single-Cell Genetic Mosaic Analysis.” <i>Cell Reports</i>, vol. 35, no. 12, 109274, Cell Press, 2021, doi:<a href=\"https://doi.org/10.1016/j.celrep.2021.109274\">10.1016/j.celrep.2021.109274</a>.","ista":"Contreras X, Amberg N, Davaatseren A, Hansen AH, Sonntag J, Andersen L, Bernthaler T, Streicher C, Heger A-M, Johnson RL, Schwarz LA, Luo L, Rülicke T, Hippenmeyer S. 2021. A genome-wide library of MADM mice for single-cell genetic mosaic analysis. Cell Reports. 35(12), 109274.","chicago":"Contreras, Ximena, Nicole Amberg, Amarbayasgalan Davaatseren, Andi H Hansen, Johanna Sonntag, Lill Andersen, Tina Bernthaler, et al. “A Genome-Wide Library of MADM Mice for Single-Cell Genetic Mosaic Analysis.” <i>Cell Reports</i>. Cell Press, 2021. <a href=\"https://doi.org/10.1016/j.celrep.2021.109274\">https://doi.org/10.1016/j.celrep.2021.109274</a>.","short":"X. Contreras, N. Amberg, A. Davaatseren, A.H. Hansen, J. Sonntag, L. Andersen, T. Bernthaler, C. Streicher, A.-M. Heger, R.L. Johnson, L.A. Schwarz, L. Luo, T. Rülicke, S. Hippenmeyer, Cell Reports 35 (2021).","ama":"Contreras X, Amberg N, Davaatseren A, et al. A genome-wide library of MADM mice for single-cell genetic mosaic analysis. <i>Cell Reports</i>. 2021;35(12). doi:<a href=\"https://doi.org/10.1016/j.celrep.2021.109274\">10.1016/j.celrep.2021.109274</a>","ieee":"X. Contreras <i>et al.</i>, “A genome-wide library of MADM mice for single-cell genetic mosaic analysis,” <i>Cell Reports</i>, vol. 35, no. 12. Cell Press, 2021."},"acknowledgement":"We thank the Bioimaging, Life Science, and Pre-Clinical Facilities at IST Austria; M.P. Postiglione, C. Simbriger, K. Valoskova, C. Schwayer, T. Hussain, M. Pieber, and V. Wimmer for initial experiments, technical support, and/or assistance; R. Shigemoto for sharing iv (Dnah11 mutant) mice; and M. Sixt and all members of the Hippenmeyer lab for discussion. This work was supported by National Institutes of Health grants ( R01-NS050580 to L.L. and F32MH096361 to L.A.S.). L.L. is an investigator of HHMI. N.A. received support from FWF Firnberg-Programm ( T 1031 ). A.H.H. is a recipient of a DOC Fellowship (24812) of the Austrian Academy of Sciences . This work also received support from IST Austria institutional funds , FWF SFB F78 to S.H., the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme ( FP7/2007-2013 ) under REA grant agreement no 618444 to S.H., and the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 725780 LinPro ) to S.H.","language":[{"iso":"eng"}],"issue":"12","title":"A genome-wide library of MADM mice for single-cell genetic mosaic analysis","pmid":1,"type":"journal_article","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"PreCl"}],"publisher":"Cell Press"}]