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While the function of the isthmic organizer at themid-hindbrain boundary has been subject to extensive experimental studies, itremains unclear how this well-defined spatial gene expression pattern, which isessential for proper isthmic organizer function, is established during vertebratedevelopment. Because the secreted Wnt1 protein plays a prominent role in isthmicorganizer function, we focused in particular on the refinement of <jats:italic>Wnt1<\/jats:italic>gene expression in this context.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We analyzed the dynamics of the corresponding murine gene regulatory network andthe related, diffusive signaling proteins using a macroscopic model for thebiological <jats:italic>two-scale signaling process<\/jats:italic>. Despite the discontinuity arisingfrom the sharp gene expression domain boundaries, we proved the existence ofunique, positive solutions for the partial differential equation system. Thisenabled the numerically and analytically analysis of the formation and stabilityof the expression pattern. Notably, the calculated expression domain of<jats:italic>Wnt1<\/jats:italic> has no sharp boundary in contrast to experimental evidence. Wesubsequently propose a post-transcriptional regulatory mechanism for <jats:italic>Wnt1<\/jats:italic>miRNAs which yields the observed sharp expression domain boundaries. Weestablished a list of candidate miRNAs and confirmed their expression pattern byradioactive in situ hybridization. The miRNA <jats:italic>miR-709<\/jats:italic> was identified as apotential regulator of <jats:italic>Wnt1<\/jats:italic> mRNA, which was validated by luciferasesensor assays.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>In summary, our theoretical analysis of the gene expression pattern induction atthe mid-hindbrain boundary revealed the need to extend the model by an additional<jats:italic>Wnt1<\/jats:italic> regulation. The developed macroscopic model of a two-scaleprocess facilitate the stringent analysis of other morphogen-based patterningprocesses.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-7-48","type":"journal-article","created":{"date-parts":[[2013,6,25]],"date-time":"2013-06-25T10:58:42Z","timestamp":1372157922000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Sharpening of expression domains induced by transcription and microRNA regulationwithin a spatio-temporal model of mid-hindbrain boundary formation"],"prefix":"10.1186","volume":"7","author":[{"given":"Sabrina","family":"Hock","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen-Kar","family":"Ng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Hasenauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominik","family":"Wittmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominik","family":"Lutter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dietrich","family":"Tr\u00fcmbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Wurst","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nilima","family":"Prakash","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabian J","family":"Theis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2013,6,25]]},"reference":[{"issue":"6078","key":"1100_CR1","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1126\/science.1215478","volume":"336","author":"L Morelli","year":"2012","unstructured":"Morelli L, Uriu K, Ares S, Oates A: Computational approaches to developmental patterning. 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