Development of five digits is controlled by a bipartite long-range cis-regulator

Laura A Lettice, Iain Williamson, Paul S Devenney, Fiona Kilanowski, Julia Dorin, Robert E Hill

Research output: Contribution to journalArticlepeer-review

Abstract

Conservation within intergenic DNA often highlights regulatory elements that control gene expression from a long range. How conservation within a single element relates to regulatory information and how internal composition relates to function is unknown. Here, we examine the structural features of the highly conserved ZRS (also called MFCS1) cis-regulator responsible for the spatiotemporal control of Shh in the limb bud. By systematically dissecting the ZRS, both in transgenic assays and within in the endogenous locus, we show that the ZRS is, in effect, composed of two distinct domains of activity: one domain directs spatiotemporal activity but functions predominantly from a short range, whereas a second domain is required to promote long-range activity. We show further that these two domains encode activities that are highly integrated and that the second domain is crucial in promoting the chromosomal conformational changes correlated with gene activity. During limb bud development, these activities encoded by the ZRS are interpreted differently by the fore limbs and the hind limbs; in the absence of the second domain there is no Shh activity in the fore limb, and in the hind limb low levels of Shh lead to a variant digit pattern ranging from two to four digits. Hence, in the embryo, the second domain stabilises the developmental programme providing a buffer for SHH morphogen activity and this ensures that five digits form in both sets of limbs.
Original languageEnglish
Pages (from-to)1715-1725
Number of pages11
JournalDevelopment
Volume141
Issue number8
Early online date8 Apr 2014
DOIs
Publication statusPublished - Apr 2014

Keywords

  • Sonic hedgehog
  • Long-range regulation
  • ZRS

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