{"day":"01","quality_controlled":"1","date_updated":"2023-08-04T09:41:08Z","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png"},"intvolume":"       149","abstract":[{"lang":"eng","text":"MicroRNAs (miRs) have an important role in tuning dynamic gene expression. However, the mechanism by which they are quantitatively controlled is unknown. We show that the amount of mature miR-9, a key regulator of neuronal development, increases during zebrafish neurogenesis in a sharp stepwise manner. We characterize the spatiotemporal profile of seven distinct microRNA primary transcripts (pri-mir)-9s that produce the same mature miR-9 and show that they are sequentially expressed during hindbrain neurogenesis. Expression of late-onset pri-mir-9-1 is added on to, rather than replacing, the expression of early onset pri-mir-9-4 and -9-5 in single cells. CRISPR/Cas9 mutation of the late-onset pri-mir-9-1 prevents the developmental increase of mature miR-9, reduces late neuronal differentiation and fails to downregulate Her6 at late stages. Mathematical modelling shows that an adaptive network containing Her6 is insensitive to linear increases in miR-9 but responds to stepwise increases of miR-9. We suggest that a sharp stepwise increase of mature miR-9 is created by sequential and additive temporal activation of distinct loci. This may be a strategy to overcome adaptation and facilitate a transition of Her6 to a new dynamic regime or steady state."}],"status":"public","related_material":{"link":[{"url":" https://github.com/burtonjosh/StepwiseMir9","relation":"software"}]},"acknowledgement":"We are grateful to Dr Tom Pettini for the advice on smiFISH technique and Dr Laure Bally-Cuif for sharing plasmids. The authors also thank the Biological Services Facility, Bioimaging and Systems Microscopy Facilities of the University of Manchester for technical support.\r\nThis work was supported by a Wellcome Trust Senior Research Fellowship (090868/Z/09/Z) and a Wellcome Trust Investigator Award (224394/Z/21/Z) to N.P. and a Medical Research Council Career Development Award to C.S.M. (MR/V032534/1). J.B. was supported by a Wellcome Trust Four-Year PhD Studentship in Basic Science (219992/Z/19/Z). Open Access funding provided by The University of Manchester. Deposited in PMC for immediate release.","isi":1,"pmid":1,"volume":149,"article_type":"original","has_accepted_license":"1","external_id":{"pmid":["36189829"],"isi":["000918161000003"]},"file":[{"success":1,"access_level":"open_access","file_id":"12438","creator":"dernst","checksum":"d7c29b74e9e4032308228cc704a30e88","file_name":"2022_Development_Soto.pdf","date_created":"2023-01-30T08:35:44Z","file_size":9348839,"date_updated":"2023-01-30T08:35:44Z","content_type":"application/pdf","relation":"main_file"}],"ddc":["570"],"year":"2022","date_published":"2022-10-01T00:00:00Z","article_processing_charge":"No","article_number":"dev200474","publication":"Development","date_created":"2023-01-16T09:53:17Z","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","department":[{"_id":"AnKi"}],"language":[{"iso":"eng"}],"file_date_updated":"2023-01-30T08:35:44Z","author":[{"first_name":"Ximena","full_name":"Soto, Ximena","last_name":"Soto"},{"last_name":"Burton","full_name":"Burton, Joshua","first_name":"Joshua"},{"last_name":"Manning","first_name":"Cerys S.","full_name":"Manning, Cerys S."},{"last_name":"Minchington","id":"7d1648cb-19e9-11eb-8e7a-f8c037fb3e3f","full_name":"Minchington, Thomas","first_name":"Thomas"},{"full_name":"Lea, Robert","first_name":"Robert","last_name":"Lea"},{"last_name":"Lee","full_name":"Lee, Jessica","first_name":"Jessica"},{"first_name":"Jochen","full_name":"Kursawe, Jochen","last_name":"Kursawe"},{"full_name":"Rattray, Magnus","first_name":"Magnus","last_name":"Rattray"},{"last_name":"Papalopulu","full_name":"Papalopulu, Nancy","first_name":"Nancy"}],"publication_status":"published","scopus_import":"1","oa":1,"publisher":"The Company of Biologists","oa_version":"Published Version","keyword":["Developmental Biology","Molecular Biology"],"citation":{"chicago":"Soto, Ximena, Joshua Burton, Cerys S. Manning, Thomas Minchington, Robert Lea, Jessica Lee, Jochen Kursawe, Magnus Rattray, and Nancy Papalopulu. “Sequential and Additive Expression of MiR-9 Precursors Control Timing of Neurogenesis.” <i>Development</i>. The Company of Biologists, 2022. <a href=\"https://doi.org/10.1242/dev.200474\">https://doi.org/10.1242/dev.200474</a>.","mla":"Soto, Ximena, et al. “Sequential and Additive Expression of MiR-9 Precursors Control Timing of Neurogenesis.” <i>Development</i>, vol. 149, no. 19, dev200474, The Company of Biologists, 2022, doi:<a href=\"https://doi.org/10.1242/dev.200474\">10.1242/dev.200474</a>.","ieee":"X. Soto <i>et al.</i>, “Sequential and additive expression of miR-9 precursors control timing of neurogenesis,” <i>Development</i>, vol. 149, no. 19. The Company of Biologists, 2022.","ama":"Soto X, Burton J, Manning CS, et al. Sequential and additive expression of miR-9 precursors control timing of neurogenesis. <i>Development</i>. 2022;149(19). doi:<a href=\"https://doi.org/10.1242/dev.200474\">10.1242/dev.200474</a>","ista":"Soto X, Burton J, Manning CS, Minchington T, Lea R, Lee J, Kursawe J, Rattray M, Papalopulu N. 2022. Sequential and additive expression of miR-9 precursors control timing of neurogenesis. Development. 149(19), dev200474.","apa":"Soto, X., Burton, J., Manning, C. S., Minchington, T., Lea, R., Lee, J., … Papalopulu, N. (2022). Sequential and additive expression of miR-9 precursors control timing of neurogenesis. <i>Development</i>. The Company of Biologists. <a href=\"https://doi.org/10.1242/dev.200474\">https://doi.org/10.1242/dev.200474</a>","short":"X. Soto, J. Burton, C.S. Manning, T. Minchington, R. Lea, J. Lee, J. Kursawe, M. Rattray, N. Papalopulu, Development 149 (2022)."},"type":"journal_article","publication_identifier":{"eissn":["1477-9129"],"issn":["0950-1991"]},"doi":"10.1242/dev.200474","_id":"12245","issue":"19","title":"Sequential and additive expression of miR-9 precursors control timing of neurogenesis","month":"10"}