Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud.
The zinc finger transcription factor GLI3 is considered a repressor of vertebrate Hedgehog (Hh) signaling. In humans, the absence of GLI3 function causes Greig cephalopolysyndactyly syndrome, affecting the development of the brain, eye, face, and limb. Because the etiology of these malformations is not well understood, we examined the phenotype of mouse Gli3-/- mutants as a model to investigate this. We observed an up-regulation of Fgf8 in the anterior neural ridge, isthmus, eye, facial primordia, and limb buds of mutant embryos, sites coinciding with the human disease. Intriguingly, endogenous apoptosis was reduced in Fgf8-positive areas in Gli3-/- mutants. Since SHH is thought to be involved in Fgf8 regulation, we compared Fgf8 expression in Shh-/- and Gli3-/-;Shh-/- mutant embryos. Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH. In the limb bud, we provide evidence that ectopic expression of Gremlin in Gli3-/- mutants might contribute to a decrease in apoptosis. Together, our data reveal that GLI3 limits Fgf8-expression domains in multiple tissues, through a mechanism that may include the induction or maintenance of apoptosis.
Aoto
Kazushi
K
Molecular Neuropathology Group, Brain Science Institute, The Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Nishimura
Tamiko
T
Eto
Kazuhiro
K
Motoyama
Jun
J
D000818:Animals; D017209:Apoptosis; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D001921:Brain / Q000002:abnormalities / Q000196:embryology*; D016207:Cytokines; D004268:DNA-Binding Proteins / Q000502:physiology*; D005145:Face / Q000002:abnormalities / Q000196:embryology*; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D018878:Limb Buds / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins; D011506:Proteins / Q000235:genetics; D012097:Repressor Proteins; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3
D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D011506:Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3; C113178:Grem1 protein, mouse; C496457:Fgf8 protein, mouse; C108003:GLI3 protein, Xenopus; C065683:GLI3 protein, human; C486400:GREM1 protein, Xenopus; C486399:GREM1 protein, human; C465571:Gli3 protein, mouse; C465570:Shh protein, mouse