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In mammals there are six H3K4 methyltransferases related to yeast Set1 and fly Trithorax, including two orthologs of fly Trithorax-related: MLL3 and MLL4. Exome sequencing has documented high frequencies of MLL3 and MLL4 mutations in many types of human cancer. Despite this emerging importance, the requirements of these paralogs in mammalian development have only been incompletely reported. Here we examined the null phenotypes to establish that MLL3 is first required for lung maturation whereas MLL4 is first required for migration of the anterior visceral endoderm (AVE) that initiates gastrulation. This collective cell migration is preceded by a columnar to squamous transition in visceral endoderm cells that depends on MLL4. Furthermore, Mll4 mutants display incompletely penetrant, sex distorted, embryonic haploinsufficiency and adult heterozygous mutants show aspects of Kabuki syndrome, indicating that MLL4 action, unlike MLL3, is dosage dependent. The highly specific and discordant functions of these paralogs in mouse development argues against their action as general enhancer factors.<\/jats:p>","DOI":"10.1242\/dev.186999","type":"journal-article","created":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T20:15:21Z","timestamp":1590092121000},"source":"Crossref","is-referenced-by-count":32,"title":["MLL4 is required after implantation whereas MLL3 becomes essential during late gestation"],"prefix":"10.1242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5862-4882","authenticated-orcid":false,"given":"Deepthi","family":"Ashokkumar","sequence":"first","affiliation":[{"name":"Genomics, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universit\u00e4t Dresden, Tatzberg 47, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8292-938X","authenticated-orcid":false,"given":"Qinyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Genomics, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universit\u00e4t Dresden, Tatzberg 47, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1644-8200","authenticated-orcid":false,"given":"Christian","family":"Much","sequence":"additional","affiliation":[{"name":"Genomics, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universit\u00e4t Dresden, Tatzberg 47, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita S.","family":"Bledau","sequence":"additional","affiliation":[{"name":"Stem Cell Engineering, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universit\u00e4t Dresden, Tatzberg 47, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Naumann","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Molecular Cell Biology and Genetics, Transgenic Core Facility, Pfotenhauerstr. 108, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitra","family":"Alexopoulou","sequence":"additional","affiliation":[{"name":"DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering, Technische Universit\u00e4t Dresden, Fetscherstr. 105, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2668-8371","authenticated-orcid":false,"given":"Andreas","family":"Dahl","sequence":"additional","affiliation":[{"name":"DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering, Technische Universit\u00e4t Dresden, Fetscherstr. 105, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Goveas","sequence":"additional","affiliation":[{"name":"Genomics, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universit\u00e4t Dresden, Tatzberg 47, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Fu","sequence":"additional","affiliation":[{"name":"Genomics, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universit\u00e4t Dresden, Tatzberg 47, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Anastassiadis","sequence":"additional","affiliation":[{"name":"Stem Cell Engineering, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universit\u00e4t Dresden, Tatzberg 47, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Francis","family":"Stewart","sequence":"additional","affiliation":[{"name":"Genomics, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universit\u00e4t Dresden, Tatzberg 47, 01307 Dresden, Germany"},{"name":"Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7481-0220","authenticated-orcid":false,"given":"Andrea","family":"Kranz","sequence":"additional","affiliation":[{"name":"Genomics, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universit\u00e4t Dresden, Tatzberg 47, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,1,1]]},"reference":[{"key":"2021042623461976300_DEV186999C1","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1242\/dev.072728","article-title":"Differential regulation of node formation, nodal ciliogenesis and cilia positioning by Noto and Foxj1","volume":"139","author":"Alten","year":"2012","journal-title":"Development"},{"key":"2021042623461976300_DEV186999C2","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1242\/dmm.003087","article-title":"Dre recombinase, like Cre, is a highly efficient site-specific recombinase in E. coli, mammalian cells and mice","volume":"2","author":"Anastassiadis","year":"2009","journal-title":"Dis. 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