{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:12:57Z","timestamp":1791353577681,"version":"4.3.1"},"reference-count":85,"publisher":"The Company of Biologists","issue":"8","license":[{"start":{"date-parts":[[2000,4,15]],"date-time":"2000-04-15T00:00:00Z","timestamp":955756800000},"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":[[2000,4,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The secreted factor Sonic hedgehog (SHH) is both required for and sufficient to induce multiple developmental processes, including ventralization of the CNS, branching morphogenesis of the lungs and anteroposterior patterning of the limbs. Based on analogy to the Drosophila Hh pathway, the multiple GLI transcription factors in vertebrates are likely to both transduce SHH signaling and repress Shh transcription. In order to discriminate between overlapping versus unique requirements for the three Gli genes in mice, we have produced a Gli1 mutant and analyzed the phenotypes of Gli1\/Gli2 and Gli1\/3 double mutants. Gli3xt mutants have polydactyly and dorsal CNS defects associated with ectopic Shh expression, indicating GLI3 plays a role in repressing Shh. In contrast, Gli2 mutants have five digits, but lack a floorplate, indicating that it is required to transduce SHH signaling in some tissues. Remarkably, mice homozygous for a Gli1zfd mutation that deletes the exons encoding the DNA-binding domain are viable and appear normal. Transgenic mice expressing a GLI1 protein lacking the zinc fingers can not induce SHH targets in the dorsal brain, indicating that the Gli1zfd allele contains a hypomorphic or null mutation. Interestingly, Gli1zfd\/zfd;Gli2zfd\/+, but not Gli1zfd\/zfd;Gli3zfd\/+ double mutants have a severe phenotype; most Gli1zfd\/zfd;Gli2zfd\/+ mice die soon after birth and all have multiple defects including a variable loss of ventral spinal cord cells and smaller lungs that are similar to, but less extreme than, Gli2zfd\/zfd mutants. Gli1\/Gli2 double homozygous mutants have more extreme CNS and lung defects than Gli1zfd\/zfd;Gli2zfd\/+ mutants, however, in contrast to Shh mutants, ventrolateral neurons develop in the CNS and the limbs have 5 digits with an extra postaxial nubbin. These studies demonstrate that the zinc-finger DNA-binding domain of GLI1 protein is not required for SHH signaling in mouse. Furthermore, Gli1 and Gli2, but not Gli1 and Gli3, have extensive overlapping functions that are likely downstream of SHH signaling.<\/jats:p>","DOI":"10.1242\/dev.127.8.1593","type":"journal-article","created":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T16:02:14Z","timestamp":1619193734000},"page":"1593-1605","source":"Crossref","is-referenced-by-count":648,"title":["Mouse\n                    <i>Gli1<\/i>\n                    mutants are viable but have defects in SHH signaling in combination with a\n                    <i>Gli2<\/i>\n                    mutation"],"prefix":"10.1242","volume":"127","author":[{"given":"H. L.","family":"Park","sequence":"first","affiliation":[{"name":"1 Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University Medical School, 540 First Ave., New York, NY 10016, USA"},{"name":"2 Department of Cell Biology and New York University Medical School, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Bai","sequence":"additional","affiliation":[{"name":"1 Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University Medical School, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. A.","family":"Platt","sequence":"additional","affiliation":[{"name":"1 Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University Medical School, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. P.","family":"Matise","sequence":"additional","affiliation":[{"name":"1 Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University Medical School, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Beeghly","sequence":"additional","affiliation":[{"name":"1 Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University Medical School, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. c.","family":"Hui","sequence":"additional","affiliation":[{"name":"4 Program in Developmental Biology, The Hospital for Sick Children, and Program in Molecular and Medical Genetics, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Nakashima","sequence":"additional","affiliation":[{"name":"1 Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University Medical School, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. L.","family":"Joyner","sequence":"additional","affiliation":[{"name":"1 Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University Medical School, 540 First Ave., New York, NY 10016, USA"},{"name":"2 Department of Cell Biology and New York University Medical School, 540 First Ave., New York, NY 10016, USA"},{"name":"3 Physiology and Neuroscience, New York University Medical School, 540 First Ave., New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2000,4,15]]},"reference":[{"key":"2023051200243775400_DEVELOP_127_8_1593C1","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1101\/gad.10.16.2003","article-title":"Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the Cubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins","volume":"10","author":"Alexandre","year":"1996","journal-title":"Genes Dev"},{"key":"2023051200243775400_DEVELOP_127_8_1593C2","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/S0092-8674(00)80292-5","article-title":"Proteolysis that is inhibited by hedgehog targets cubitus interruptus protein to the nucleus and converts it to a repressor","volume":"89","author":"Aza-Blanc","year":"1997","journal-title":"Cell"},{"key":"2023051200243775400_DEVELOP_127_8_1593C3","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1038\/368208a0","article-title":"Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein","volume":"368","author":"Basler","year":"1994","journal-title":"Nature"},{"key":"2023051200243775400_DEVELOP_127_8_1593C4","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1242\/dev.124.1.53","article-title":"Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis","volume":"124","author":"Bellusci","year":"1997","journal-title":"Development"},{"key":"2023051200243775400_DEVELOP_127_8_1593C5","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/S0960-9822(02)00480-3","article-title":"Sertoli cell signaling by Desert hedgehog regulates the male germline","volume":"6","author":"Bitgood","year":"1996","journal-title":"Current Biol"},{"key":"2023051200243775400_DEVELOP_127_8_1593C6","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1006\/dbio.1995.0010","article-title":"Hedgehog an Bmp Genes Are Coexpressed at Many Diverse Sites of Cell-Cell Interaction in the Mouse Embryo","volume":"172","author":"Bitgood","year":"1995","journal-title":"Dev. 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