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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Opposing Functions of the ETS Factor Family Define Shh Spatial Expression in Limb Buds and Underlie Polydactyly
AU - Lettice, Laura A.
AU - Williamson, Iain
AU - Wiltshire, John H.
AU - Peluso, Silvia
AU - Devenney, Paul S.
AU - Hill, Alison E.
AU - Essafi, Abdelkader
AU - Hagman, James
AU - Mort, Richard
AU - Grimes, Graeme
AU - DeAngelis, Carlo L.
AU - Hill, Robert E.
PY - 2012/2/14
Y1 - 2012/2/14
N2 - Sonic hedgehog (Shh) expression during limb development is crucial for specifying the identity and number of digits. The spatial pattern of Shh expression is restricted to a region called the zone of polarizing activity (ZPA), and this expression is controlled from a long distance by the cis-regulator ZRS. Here, members of two groups of ETS transcription factors are shown to act directly at the ZRS mediatinga differential effect on Shh, defining its spatial expression pattern. Occupancy at multiple GABPα/ETS1 sites regulates the position of the ZPA boundary, whereas ETV4/ETV5 binding restricts expression outside the ZPA. The ETS gene family is therefore attributed with specifying the boundaries of the classical ZPA. Two point mutations within the ZRS change the profile of ETS binding and activate Shh expression at an ectopic site in the limb bud. These molecular changes define a pathogenetic mechanism that leads to preaxial polydactyly (PPD). A long-range limb-specific enhancer controls Sonic hedgehog expression in a spatiotemporally restricted manner. Lettice etal. identify ETS-binding sites within this enhancer that mediate antagonistic interactions between different ETS transcription factor clades. Mutations in the enhancer that change the balance of power between ETS factors cause limb abnormalities.
AB - Sonic hedgehog (Shh) expression during limb development is crucial for specifying the identity and number of digits. The spatial pattern of Shh expression is restricted to a region called the zone of polarizing activity (ZPA), and this expression is controlled from a long distance by the cis-regulator ZRS. Here, members of two groups of ETS transcription factors are shown to act directly at the ZRS mediatinga differential effect on Shh, defining its spatial expression pattern. Occupancy at multiple GABPα/ETS1 sites regulates the position of the ZPA boundary, whereas ETV4/ETV5 binding restricts expression outside the ZPA. The ETS gene family is therefore attributed with specifying the boundaries of the classical ZPA. Two point mutations within the ZRS change the profile of ETS binding and activate Shh expression at an ectopic site in the limb bud. These molecular changes define a pathogenetic mechanism that leads to preaxial polydactyly (PPD). A long-range limb-specific enhancer controls Sonic hedgehog expression in a spatiotemporally restricted manner. Lettice etal. identify ETS-binding sites within this enhancer that mediate antagonistic interactions between different ETS transcription factor clades. Mutations in the enhancer that change the balance of power between ETS factors cause limb abnormalities.
U2 - 10.1016/j.devcel.2011.12.010
DO - 10.1016/j.devcel.2011.12.010
M3 - Journal article
C2 - 22340503
AN - SCOPUS:84856995675
VL - 22
SP - 459
EP - 467
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
IS - 2
ER -