{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:35:01Z","timestamp":1791326101699,"version":"4.3.1"},"reference-count":49,"publisher":"The Company of Biologists","issue":"22","license":[{"start":{"date-parts":[[1998,11,15]],"date-time":"1998-11-15T00:00:00Z","timestamp":911088000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1998,11,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>The Engrailed-1 gene, En1, a murine homologue of the Drosophila homeobox gene engrailed (en), is required for midbrain and cerebellum development and dorsal\/ventral patterning of the limbs. In Drosophila, en is involved in regulating a number of key patterning processes including segmentation of the epidermis. An important question is whether, during evolution, the biochemical properties of En proteins have been conserved, revealing a common underlying molecular mechanism to their diverse developmental activities. To address this question, we have replaced the coding sequences of En1 with Drosophila en. Mice expressing Drosophila en in place of En1 have a near complete rescue of the lethal En1 mutant brain defect and most skeletal abnormalities. In contrast, expression of Drosophila en in the embryonic limbs of En1 mutants does not lead to repression of Wnt7a in the embryonic ventral ectoderm or full rescue of the embryonic dorsal\/ventral patterning defects. Furthermore, neither En2 nor en rescue the postnatal limb abnormalities that develop in rare En1 null mutants that survive. These studies demonstrate that the biochemical activity utilized in mouse to mediate brain development has been retained by Engrailed proteins across the phyla, and indicate that during evolution vertebrate En proteins have acquired two unique functions during embryonic and postnatal limb development and that only En1 can function postnatally.<\/jats:p>","DOI":"10.1242\/dev.125.22.4521","type":"journal-article","created":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T03:29:10Z","timestamp":1619407750000},"page":"4521-4530","source":"Crossref","is-referenced-by-count":88,"title":["<i>Drosophila engrailed<\/i> can substitute for mouse <i>Engrailed1<\/i> function in mid-hindbrain, but not limb development"],"prefix":"10.1242","volume":"125","author":[{"given":"Mark C.","family":"Hanks","sequence":"first","affiliation":[{"name":"1 Developmental Genetics Program and Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine and Departments of Cell Biology and Physiology and Neuroscience, NYU Medical Center, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Loomis","sequence":"additional","affiliation":[{"name":"1 Developmental Genetics Program and Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine and Departments of Cell Biology and Physiology and Neuroscience, NYU Medical Center, 540 First Ave., New York, NY 10016, USA"},{"name":"2 Ronald O. Perelman Department of Dermatology and Department of Cell Biology, NYU Medical School, 550 First Avenue, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Harris","sequence":"additional","affiliation":[{"name":"1 Developmental Genetics Program and Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine and Departments of Cell Biology and Physiology and Neuroscience, NYU Medical Center, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Xiang","family":"Tong","sequence":"additional","affiliation":[{"name":"2 Ronald O. Perelman Department of Dermatology and Department of Cell Biology, NYU Medical School, 550 First Avenue, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Anson-Cartwright","sequence":"additional","affiliation":[{"name":"3 Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute, Mt Sinai Hospital, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Auerbach","sequence":"additional","affiliation":[{"name":"1 Developmental Genetics Program and Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine and Departments of Cell Biology and Physiology and Neuroscience, NYU Medical Center, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Joyner","sequence":"additional","affiliation":[{"name":"1 Developmental Genetics Program and Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine and Departments of Cell Biology and Physiology and Neuroscience, NYU Medical Center, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[1998,11,15]]},"reference":[{"key":"2025021504003170800_DEVELOP_125_22_4521C1","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1242\/dev.125.9.1691","article-title":"Murine Otx1 and Drosophila otd genes share conserved genetic functions required in invertebrate and vertebrate brain development","volume":"125","author":"Acampora","year":"1998","journal-title":"Development"},{"key":"2025021504003170800_DEVELOP_125_22_4521C2","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1002\/j.1460-2075.1994.tb06462.x","article-title":"Conservation of a functional hierarchy between mammalian and insect Hox\/HOM genes","volume":"13","author":"Bachiller","year":"1994","journal-title":"EMBO J"},{"key":"2025021504003170800_DEVELOP_125_22_4521C3","doi-asserted-by":"publisher","first-page":"5021","DOI":"10.1242\/dev.124.24.5021","article-title":"Novel regulatory interactions revealed by studies of murine limb pattern in Wnt-7a and En1 mutants","volume":"124","author":"Cygan","year":"1997","journal-title":"Development"},{"key":"2025021504003170800_DEVELOP_125_22_4521C4","doi-asserted-by":"publisher","first-page":"3490","DOI":"10.1523\/JNEUROSCI.15-05-03490.1995","article-title":"Conditional rescue of the dunce learning\/memory and female fertility defects with Drosophila or rat transgenes","volume":"15","author":"Dauwalder","year":"1995","journal-title":"J. Neurosci"},{"key":"2025021504003170800_DEVELOP_125_22_4521C5","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1101\/gad.2.12b.1736","article-title":"Expression patterns of the homeo box- containing genes En1 and En2 and the proto-oncogene int-1 diverge during mouse development","volume":"2","author":"Davis","year":"1988","journal-title":"Genes Dev"},{"key":"2025021504003170800_DEVELOP_125_22_4521C6","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1242\/dev.111.2.287","article-title":"Examining pattern formation in mouse, chicken and frog embryos with an En-specific antiserum","volume":"111","author":"Davis","year":"1991","journal-title":"Development"},{"key":"2025021504003170800_DEVELOP_125_22_4521C7","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1038\/318630a0","article-title":"The Drosophila developmental gene, engrailed, encodes a sequence-specific DNA binding activity","volume":"318","author":"Desplan","year":"1985","journal-title":"Nature"},{"key":"2025021504003170800_DEVELOP_125_22_4521C8","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1016\/0092-8674(88)90123-7","article-title":"The sequence specificity of homeodomain-DNA interaction","volume":"54","author":"Desplan","year":"1988","journal-title":"Cell"},{"key":"2025021504003170800_DEVELOP_125_22_4521C9","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1101\/gad.4.6.1068","article-title":"Repression of ci-D in posterior compartments of Drosophila by engrailed","volume":"4","author":"Eaton","year":"1990","journal-title":"Genes Dev"},{"key":"2025021504003170800_DEVELOP_125_22_4521C10","doi-asserted-by":"publisher","first-page":"2723","DOI":"10.1002\/j.1460-2075.1993.tb05934.x","article-title":"Functional domains of the Drosophila Engrailed protein","volume":"12","author":"Han","year":"1993","journal-title":"EMBO J"},{"key":"2025021504003170800_DEVELOP_125_22_4521C11","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1126\/science.7624797","article-title":"Rescue of the En1 mutant phenotype by replacement of En1 with En2","volume":"4","author":"Hanks","year":"1995","journal-title":"Science"},{"key":"2025021504003170800_DEVELOP_125_22_4521C12","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1038\/332858a0","article-title":"Divergent homeo box proteins recognize similar DNA sequences in Drosophila","volume":"332","author":"Hoey","year":"1988","journal-title":"Nature"},{"key":"2025021504003170800_DEVELOP_125_22_4521C13","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/0092-8674(92)90467-Q","article-title":"Boundaries and fields in early embryos","volume":"68","author":"Ingham","year":"1992","journal-title":"Cell"},{"key":"2025021504003170800_DEVELOP_125_22_4521C14","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1038\/336744a0","article-title":"Activation and repression of transcription by homoeodomain-containing proteins that bind a common site","volume":"336","author":"Jaynes","year":"1988","journal-title":"Nature"},{"key":"2025021504003170800_DEVELOP_125_22_4521C15","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1002\/j.1460-2075.1991.tb07663.x","article-title":"Active repression of transcription by the Engrailed homeodomain protein","volume":"10","author":"Jaynes","year":"1991","journal-title":"EMBO J"},{"key":"2025021504003170800_DEVELOP_125_22_4521C16","doi-asserted-by":"publisher","first-page":"3072","DOI":"10.1101\/gad.11.22.3072","article-title":"Groucho acts as a corepressor for a subset of negative regulators, including Hairy and Engrailed","volume":"11","author":"Jimenez","year":"1997","journal-title":"Genes Dev"},{"key":"2025021504003170800_DEVELOP_125_22_4521C17","first-page":"15","volume":"12","author":"Joyner","year":"1996","journal-title":"Engrailed, Wnt and Pax genes regulate midbrain- hindbrain development. Trends Genet"},{"key":"2025021504003170800_DEVELOP_125_22_4521C18","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1126\/science.1672471","article-title":"Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En2 homeobox","volume":"251","author":"Joyner","year":"1991","journal-title":"Science"},{"key":"2025021504003170800_DEVELOP_125_22_4521C19","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1016\/0092-8674(89)90341-3","article-title":"Transcriptional activation and repression by Ultrabithorax proteins in cultured Drosophila cells","volume":"57","author":"Krasnow","year":"1989","journal-title":"Cell"},{"key":"2025021504003170800_DEVELOP_125_22_4521C20","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1002\/dvg.1020130505","article-title":"Cloning and sequence comparison of the mouse, human, and chicken engrailed genes reveal potential functional domains and regulatory regions","volume":"13","author":"Logan","year":"1992","journal-title":"Dev. Genet"},{"key":"2025021504003170800_DEVELOP_125_22_4521C21","doi-asserted-by":"publisher","first-page":"2317","DOI":"10.1242\/dev.124.12.2317","article-title":"The role of Engrailed in establishing the dorsoventral axis of the chick limb","volume":"124","author":"Logan","year":"1997","journal-title":"Development"},{"key":"2025021504003170800_DEVELOP_125_22_4521C22","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/382360a0","article-title":"The mouse Engrailed-1 gene and ventral limb patterning","volume":"382","author":"Loomis","year":"1996","journal-title":"Nature"},{"key":"2025021504003170800_DEVELOP_125_22_4521C23","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1242\/dev.125.6.1137","article-title":"Analysis of the genetic pathway leading to formation of ectopic ectodermal ridges in mouse Engrailed-1 mutant limbs","volume":"125","author":"Loomis","year":"1998","journal-title":"Development"},{"key":"2025021504003170800_DEVELOP_125_22_4521C24","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1038\/359835a0","article-title":"Homeotic transformation of the occipital bones of the skull by ectopic expression of a homeobox gene","volume":"359","author":"Lufkin","year":"1992","journal-title":"Nature"},{"key":"2025021504003170800_DEVELOP_125_22_4521C25","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/0925-4773(93)90003-G","article-title":"Functional analysis of the mouse homeobox gene HoxB9 in Drosophila development","volume":"42","author":"Malicki","year":"1993","journal-title":"Mech. Dev"},{"key":"2025021504003170800_DEVELOP_125_22_4521C26","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1016\/0092-8674(90)90499-5","article-title":"Mouse Hox-2.2 specifies thoracic segmental identify in Drosophila embryos and larvae","volume":"63","author":"Malicki","year":"1990","journal-title":"Cell"},{"key":"2025021504003170800_DEVELOP_125_22_4521C27","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1016\/0092-8674(90)90500-E","article-title":"Human Hox-4.2 and Drosophila deformed encode similar regulatory specificities in Drosophila embryos and larvae","volume":"63","author":"McGinnis","year":"1990","journal-title":"Cell"},{"key":"2025021504003170800_DEVELOP_125_22_4521C28","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/0092-8674(92)90222-X","article-title":"The midbrain-hindbrain phenotype of Wnt-1-\/Wnt-11 mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum","volume":"69","author":"McMahon","year":"1992","journal-title":"Cell"},{"key":"2025021504003170800_DEVELOP_125_22_4521C29","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1242\/dev.120.3.695","article-title":"Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants","volume":"120","author":"Millen","year":"1994","journal-title":"Development"},{"key":"2025021504003170800_DEVELOP_125_22_4521C30","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/S0168-9525(97)01093-7","article-title":"WNTs modulate cell fate and behavior during vertebrate development","volume":"13","author":"Moon","year":"1997","journal-title":"Trends Genet"},{"key":"2025021504003170800_DEVELOP_125_22_4521C31","doi-asserted-by":"publisher","first-page":"8424","DOI":"10.1073\/pnas.90.18.8424","article-title":"Derivation of completely cell culture-derived mice from early-passage embryonic stem cells","volume":"90","author":"Nagy","year":"1993","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"2025021504003170800_DEVELOP_125_22_4521C32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0092-8674(00)81073-9","article-title":"Know your neighbors: three phenotypes in null mutants of the myuogenic bHLH gene MRF4","volume":"85","author":"Olson","year":"1996","journal-title":"Cell"},{"key":"2025021504003170800_DEVELOP_125_22_4521C33","doi-asserted-by":"publisher","first-page":"3385","DOI":"10.1002\/j.1460-2075.1996.tb00704.x","article-title":"Engrailed and Hox homeodomain proteins contain a related Pbx interaction motif that recognized a common structure present in Pbx","volume":"15","author":"Peltenburg","year":"1996","journal-title":"EMBO J"},{"key":"2025021504003170800_DEVELOP_125_22_4521C34","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1016\/0092-8674(94)90351-4","article-title":"The genetic basis of patterned baldness in Drosophila","volume":"76","author":"Perrimon","year":"1994","journal-title":"Cell"},{"key":"2025021504003170800_DEVELOP_125_22_4521C35","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1101\/gad.4.7.1209","article-title":"Mutations in the Drosophila gene extradenticle affect the way specific homeo domain proteins regulate segmental identity","volume":"4","author":"Pfeifer","year":"1990","journal-title":"Genes Dev"},{"key":"2025021504003170800_DEVELOP_125_22_4521C36","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/0092-8674(85)90306-X","article-title":"The engrailed locus of Drosophila: structural analysis of an embryonic transcript","volume":"40","author":"Poole","year":"1985","journal-title":"Cell"},{"key":"2025021504003170800_DEVELOP_125_22_4521C37","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/0168-9525(89)90102-9","article-title":"Towards a molecular genetic analysis of mammalian development","volume":"5","author":"Rossant","year":"1989","journal-title":"Trends Genet"},{"key":"2025021504003170800_DEVELOP_125_22_4521C38","first-page":"353","article-title":"Cell lines derived from late embryonic stages of Drosophila melanogaster","volume":"27","author":"Schneider","year":"1972","journal-title":"J. Embryol. Exp. Morphol"},{"key":"2025021504003170800_DEVELOP_125_22_4521C39","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1242\/dev.121.6.1625","article-title":"Analysis of cubitus interruptus regulation in Drosophila embryos and imaginal disks","volume":"121","author":"Schwartz","year":"1995","journal-title":"Development"},{"key":"2025021504003170800_DEVELOP_125_22_4521C40","doi-asserted-by":"publisher","first-page":"3141","DOI":"10.1242\/dev.122.10.3141","article-title":"A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo","volume":"122","author":"Smith","year":"1996","journal-title":"Development"},{"key":"2025021504003170800_DEVELOP_125_22_4521C41","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1126\/science.3399892","article-title":"Cloning of a lymphoid-specific cDNA encoding a protein binding the regulatory octamer DNA motif","volume":"241","author":"Staudt","year":"1988","journal-title":"Science"},{"key":"2025021504003170800_DEVELOP_125_22_4521C42","doi-asserted-by":"publisher","first-page":"2804","DOI":"10.1128\/MCB.18.5.2804","article-title":"Two distinct types of repression domain in engrailed: one interacts with the groucho corepressor and is preferentially active on integrated target genes","volume":"18","author":"Tolkunova","year":"1998","journal-title":"Mol. Cell Biol"},{"key":"2025021504003170800_DEVELOP_125_22_4521C43","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/0925-4773(95)00394-G","article-title":"Hox gene products modulate the DNA binding activity of Pbx1 and Pbx2","volume":"52","author":"van Dijk","year":"1995","journal-title":"Mech. Dev"},{"key":"2025021504003170800_DEVELOP_125_22_4521C44","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1016\/0092-8674(94)90526-6","article-title":"Extradenticle raises the DNA binding specificity of homeotic selector gene products","volume":"78","author":"van Dijk","year":"1994","journal-title":"Cell"},{"key":"2025021504003170800_DEVELOP_125_22_4521C45","first-page":"3","article-title":"Early mesencephalon\/metencephalon patterning and development of the cerebellum","volume":"5","author":"Wassef","year":"1997","journal-title":"Persp. Dev. Neurobiol"},{"key":"2025021504003170800_DEVELOP_125_22_4521C46","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1038\/ng1297-404","article-title":"Huntingtin is required for neurogenesis and is not impaired by the Huntingtin disease CAG expansion","volume":"17","author":"White","year":"1997","journal-title":"Nature Genet"},{"key":"2025021504003170800_DEVELOP_125_22_4521C47","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/365087a0","article-title":"Non-injection methods for the production of embryonic stem cell-embryo chimaeras","volume":"365","author":"Wood","year":"1993","journal-title":"Nature"},{"key":"2025021504003170800_DEVELOP_125_22_4521C48","doi-asserted-by":"publisher","first-page":"2065","DOI":"10.1242\/dev.120.7.2065","article-title":"Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum","volume":"120","author":"Wurst","year":"1994","journal-title":"Development"},{"key":"2025021504003170800_DEVELOP_125_22_4521C49","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1101\/gad.7.3.343","article-title":"The mouse Hox-1.3 gene is functionally equivalent to the Drosophila Sex combs reduced gene","volume":"7","author":"Zhao","year":"1993","journal-title":"Genes Dev"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/125\/22\/4521\/3140419\/develop_125_22_4521.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/125\/22\/4521\/3140419\/develop_125_22_4521.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,15]],"date-time":"2025-02-15T04:00:54Z","timestamp":1739592054000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/125\/22\/4521\/40062\/Drosophila-engrailed-can-substitute-for-mouse"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,11,15]]},"references-count":49,"journal-issue":{"issue":"22","published-print":{"date-parts":[[1998,11,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.125.22.4521","relation":{},"ISSN":["0950-1991","1477-9129"],"issn-type":[{"value":"0950-1991","type":"print"},{"value":"1477-9129","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,11,15]]}}}