Document Detail


Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation.
MedLine Citation:
PMID:  10725236     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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. Gli3(xt) 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 Gli1(zfd )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 Gli1(zfd )allele contains a hypomorphic or null mutation. Interestingly, Gli1(zfd/zfd);Gli2(zfd/+), but not Gli1(zfd/zfd);Gli3(zfd/+) double mutants have a severe phenotype; most Gli1(zfd/zfd);Gli2(zfd/+) 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, Gli2(zfd/zfd) mutants. Gli1/Gli2 double homozygous mutants have more extreme CNS and lung defects than Gli1(zfd/zfd);Gli2(zfd/+) 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.
Authors:
H L Park; C Bai; K A Platt; M P Matise; A Beeghly; C C Hui; M Nakashima; A L Joyner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  127     ISSN:  0950-1991     ISO Abbreviation:  Development     Publication Date:  2000 Apr 
Date Detail:
Created Date:  2000-06-30     Completed Date:  2000-06-30     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1593-605     Citation Subset:  IM    
Affiliation:
Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, Department of Cell Biology and Physiology and Neuroscience, New York University Medical School, New York, NY 10016, USA.
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MeSH Terms
Descriptor/Qualifier:
Abnormalities, Multiple
Alleles
Animals
Binding Sites
Brain / embryology,  metabolism
COS Cells
DNA / metabolism
DNA-Binding Proteins
Diencephalon / embryology
Embryonic and Fetal Development
Extremities / embryology
Gene Expression
Hedgehog Proteins
Humans
Kruppel-Like Transcription Factors
Lung / embryology
Mice
Mice, Transgenic
Mutagenesis
Nerve Tissue Proteins*
Notochord / embryology
Nuclear Proteins
Oncogene Proteins / genetics,  metabolism*
Proteins / genetics,  metabolism*
Repressor Proteins*
Signal Transduction / physiology*
Spinal Cord / embryology
Trans-Activators*
Transcription Factors / genetics,  metabolism*
Xenopus Proteins*
Zinc Fingers
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/GLI2 protein, human; 0/GLI3 protein, Xenopus; 0/GLI3 protein, human; 0/Gli protein; 0/Gli2 protein; 0/Gli3 protein, mouse; 0/Hedgehog Proteins; 0/Kruppel-Like Transcription Factors; 0/Nerve Tissue Proteins; 0/Nuclear Proteins; 0/Oncogene Proteins; 0/Proteins; 0/Repressor Proteins; 0/SHH protein, human; 0/Trans-Activators; 0/Transcription Factors; 0/Xenopus Proteins; 9007-49-2/DNA

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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