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restrict Hand2 expression to the posterior limb (te Welscher et al., 2002).
Correspondingly, Hand2 restricts Gli3r to the anterior aspect of the limb. This
reciprocal antagonism sets up the ZPA and Shh expression in the posterior
distal mesenchyme. Shh subsequently counters Gli3r repression by blocking
the local processing of Gli3, keeping it in its full-length activator form. In the
developing autopod, Shh and Gli3 (Gli3/Gli3r ratio) regulate the number and
identity of the digits. In the absence of Gli3, the digits increase in number,
become syndactylous, and lose their identity (Litingtung et al., 2002).
Mutations in Gli3 result in polydactyly in both mouse and humans
(Hinchcliffe, 1980; Vortkamp et al., 1991; Vortkamp et al., 1992).
A conserved cis-regulatory element, the ZPA regulatory sequence (ZRS),
is found within intron 5 of the LMBR1 gene and is required for limb-specific
SHH expression (Clark et al., 2001; Lettice et al., 2002). Misregulation of
SHH by microduplication of the ZRS and presumed anterior ectopic
expression causes Laurin-Sandrow Syndrome with tetramelic posterior
zeugopod duplication (ulnar/fibular dimelia) and mirror-image polydactyly
(Lohan et al., 2014). In a chicken model termed oligozeugodactyly (ozd), there
is a deletion of the ZRS resulting in the absence of SHH expression with a loss
of the posterior zeugopod elements and the entire autopod of the three-digit
forelimb/wing. In humans, a deletion mapping upstream of this region results
in an autosomal recessive disorder Acheiropodia (Ianakiev et al., 2001) that
causes longitudinal postaxial deficiencies resembling the limb phenotype of
ozd chicks and Shh -/- mice (Ros et al., 2003). Apart from Acheiropodia in
humans, pre-axial polydactyly (Lettice et al., 2003) triphalangeal thumb
(Heutink et al., 1994) and acropectoral syndrome (Dundar et al., 2001), are
other limb-specific disorders associated with mutations in this region.
Limb Patterning along the Dorsal-Ventral Axis (Figure 1E)
Limb dorsalization is accomplished by the release of WNT7a from the
dorsal ectoderm which induces the expression of LIM Homeobox transcription
factor 1 beta (LMX1B) in the underlying mesoderm. Expression of Engrailed
1 (EN1) in the ventral ectoderm restricts WNT7a to the dorsal ectoderm
thereby establishing the dorsal-ventral aspects of the limb. In mice lacking
Wnt7a or Lmx1b function, limbs develop with near ventral-ventral symmetry.
In contrast, over expression of Wnt7a or Lmx1b in the ventral limb generates a
dorsal-dorsal limb. Mutations that disrupt LMX1B function and cause