{"keyword":["Developmental Biology","Molecular Biology"],"volume":149,"day":"01","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","article_type":"original","abstract":[{"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.","lang":"eng"}],"oa":1,"publisher":"The Company of Biologists","tmp":{"short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"file_date_updated":"2023-01-30T08:35:44Z","related_material":{"link":[{"relation":"software","url":" https://github.com/burtonjosh/StepwiseMir9"}]},"has_accepted_license":"1","oa_version":"Published Version","publication_identifier":{"issn":["0950-1991"],"eissn":["1477-9129"]},"month":"10","doi":"10.1242/dev.200474","publication":"Development","date_published":"2022-10-01T00:00:00Z","article_number":"dev200474","quality_controlled":"1","department":[{"_id":"AnKi"}],"intvolume":"       149","scopus_import":"1","article_processing_charge":"No","date_updated":"2023-08-04T09:41:08Z","file":[{"date_updated":"2023-01-30T08:35:44Z","date_created":"2023-01-30T08:35:44Z","success":1,"checksum":"d7c29b74e9e4032308228cc704a30e88","file_size":9348839,"relation":"main_file","content_type":"application/pdf","access_level":"open_access","file_id":"12438","file_name":"2022_Development_Soto.pdf","creator":"dernst"}],"pmid":1,"status":"public","citation":{"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.","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>.","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.","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>.","short":"X. Soto, J. Burton, C.S. Manning, T. Minchington, R. Lea, J. Lee, J. Kursawe, M. Rattray, N. Papalopulu, Development 149 (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>","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>"},"type":"journal_article","title":"Sequential and additive expression of miR-9 precursors control timing of neurogenesis","year":"2022","external_id":{"pmid":["36189829"],"isi":["000918161000003"]},"isi":1,"publication_status":"published","author":[{"first_name":"Ximena","last_name":"Soto","full_name":"Soto, Ximena"},{"full_name":"Burton, Joshua","last_name":"Burton","first_name":"Joshua"},{"full_name":"Manning, Cerys S.","first_name":"Cerys S.","last_name":"Manning"},{"last_name":"Minchington","first_name":"Thomas","full_name":"Minchington, Thomas","id":"7d1648cb-19e9-11eb-8e7a-f8c037fb3e3f"},{"last_name":"Lea","first_name":"Robert","full_name":"Lea, Robert"},{"full_name":"Lee, Jessica","last_name":"Lee","first_name":"Jessica"},{"full_name":"Kursawe, Jochen","last_name":"Kursawe","first_name":"Jochen"},{"first_name":"Magnus","last_name":"Rattray","full_name":"Rattray, Magnus"},{"full_name":"Papalopulu, Nancy","last_name":"Papalopulu","first_name":"Nancy"}],"ddc":["570"],"issue":"19","language":[{"iso":"eng"}],"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.","date_created":"2023-01-16T09:53:17Z","_id":"12245"}