Opposing Functions of the ETS Factor Family Define Shh Spatial Expression in Limb Buds and Underlie Polydactyly

Laura A Lettice,Iain Williamson,John H Wiltshire,Silvia Peluso,Paul S Devenney,Alison E Hill,Abdelkader Essafi,James Hagman,Richard Mort,Graeme Grimes,Carlo L Deangelis,Robert E Hill

doi:10.1016/j.devcel.2011.12.010

Laura A Lettice, Iain Williamson + Show 10 more

Open Access

https://doi.org/10.1016/j.devcel.2011.12.010

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Abstract

SummarySonic 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 mediating a 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).

Highlights

The zone of polarizing activity (ZPA) was experimentally defined as the region located at the posterior margin of the developing limb bud that determines digit number and identity (Hill, 2007; Tickle, 2006)
The polarizing activities attributed to the ZPA are mediated by sonic hedgehog (SHH) which is postulated to act as a diffusible morphogen
None of the numerous point mutations in the ZRS that cause limb deformities fall within these conserved motifs; mutations identified in two families with preaxial polydactyly type 2 (PPD2), Family A & C (AC) (Gurnett et al, 2007) and an Australian family (AUS)

Summary

Introduction

The zone of polarizing activity (ZPA) was experimentally defined as the region located at the posterior margin of the developing limb bud that determines digit number and identity (Hill, 2007; Tickle, 2006). Single point mutations in the human ZRS are found in patients presenting with a range of limb skeletal malformations. These include preaxial polydactyly type 2 (PPD2), triphalangeal thumb polysyndactyly (TPTPS), syndactyly type IV (SD4), and Werner’s mesomelic syndrome (WMS), collectively referred to as ZRS-associated syndromes (Lettice et al, 2003, 2008; Farooq et al, 2010; Furniss et al, 2008; Gurnett et al, 2007; Semerci et al, 2009; Wieczorek et al, 2010). The point mutations function to generate ectopic expression at the anterior margin of the limb bud (Furniss et al, 2008; Lettice et al, 2008), which is the underlying cause of PPD

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