Mutation in GLI3 in postaxial polydactyly type A

Radhakrishna, Uppala; Wild, Anja; Grzeschik, Karl‐Heinz; Antonarakis, Stylianos E.

doi:10.1038/ng1197-269

Cited by 167 publications

(118 citation statements)

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“…Heterozygous mutation of sonic hedgehog is responsible for a subset of familial holoprosencephaly, a defect of the forebrain and midface (Roessler et al, 1996). Similarly, Gli3 has been implicated in three distinct developmental syndromes all of which are characterized by limb abnormalities (Kang et al, 1997;Radhakrishna et al, 1997;Vortkamp et al, 1991). In terms of tumour phenotypes, Gli1 was ®rst identi®ed by and named for its involvement in glioma formation (Kinzler et al, 1988), and Wnt1 is known to be involved in murine mammary tumorigenesis (Nusse et al, 1990).…”

Section: Hedgehog Signalling In Disease and Tumorigenesismentioning

confidence: 99%

The hedgehog signalling pathway in tumorigenesis and development

1999

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Section: Hedgehog Signalling In Disease and Tumorigenesismentioning

confidence: 99%

The hedgehog signalling pathway in tumorigenesis and development

1999

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“…These results suggest that zebrafish yot/gli2 mutations turn Gli2 into a constitutive repressor of Hh-regulated genes. Precedence for this scenario has been provided by human GLI3 mutations that result in C-terminally truncated repressor forms of GLI3 (Kang et al, 1997;Radhakrishna et al, 1997;Shin et al, 1999) and by the fact that truncated Gli proteins can act as dominant repressors in cell culture or when ectopically expressed in embryos (Ruiz i Altaba, 1999).…”

Section: C-terminal Truncations Of Gli2 Block Hedgehog Signalingmentioning

confidence: 99%

Genetic analysis of zebrafishgli1andgli2reveals divergent requirements forgligenes in vertebrate development

et al. 2003

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Gli proteins regulate the transcription of Hedgehog (Hh) target genes. Genetic studies in mouse have shown that Gli1 is not essential for embryogenesis, whereas Gli2 acts as an activator of Hh target genes. In contrast, misexpression studies in Xenopus and cultured cells have suggested that Gli1 can act as an activator of Hh-regulated genes, whereas Gli2 might function as a repressor of a subset of Hh targets. To clarify the roles of gli genes during vertebrate development, we have analyzed the requirements for gli1 and gli2 during zebrafish embryogenesis. We report that detour (dtr) mutations encode loss-of-function alleles of gli1. In contrast to mouse Gli1mutants, dtr mutants and embryos injected with gli1antisense morpholino oligonucleotides display defects in the activation of Hh target genes in the ventral neuroectoderm. Mutations in you-too(yot) encode C-terminally truncated Gli2. We find that these truncated proteins act as dominant repressors of Hh signaling, in part by blocking Gli1 function. In contrast, blocking Gli2 function by eliminating full-length Gli2 results in minor Hh signaling defects and uncovers a repressor function of Gli2 in the telencephalon. In addition, we find that Gli1 and Gli2 have activator functions during somite and neural development. These results reveal divergent requirements for Gli1 and Gli2 in mouse and zebrafish and indicate that zebrafish Gli1 is an activator of Hh-regulated genes, while zebrafish Gli2 has minor roles as a repressor or activator of Hh targets.

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“…Three types of apparently isolated polydactyly-PAP-A, PAP-A/B, and PPD-IV-are also caused by GLI3 mutations [Radhakrishna et al, 1997[Radhakrishna et al, , 1999. The major clinical findings of PHS include hypothalamic hamartoma, central and postaxial polydactyly, bifid epiglottis, imperforate anus, and renal abnormalities [Biesecker, 1993].…”

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confidence: 99%