Congenital Upper Limb Anomalies 167Figure 2. The influence of SHH/GLI3 on digit formation. This figure illustrates the
range of SHH/GLI3 signaling in two common models of limb development, chick and
mouse. A) A spontaneous mutation in chickens deletes the limb-specific enhancer of
SHH generating the Oligozeugodactyly (ozd) phenotype. Without the enhancer, no
SHH is expressed in the limbs and GLI3r function is unopposed. The unopposed GLI3r
inhibits the formation of the ulna and digits. B) In contrast, if GLI3 expression is
absent as seen in the GLI3 knockout mouse, the number of digits is excessive and the
digits lack specific AP (radioulnar) identity, including a two phalangeal thumb.
(Images courtesy of John F. Fallon, PhD, University of Wisconsin, and Maria A. Ros,
MD, PhD, Instituto de Biomedicina y Biotechnologia de Cantabria; (A) adapted with
permission from Ros et al. (Ros et al., 2003) and Oberg (Oberg, 2014).
Limb Patterning along the Anterior-Posterior Axis (Figure 1D)
The zone of polarizing activity (ZPA) is a cluster of cells in the posterior
distal mesoderm of the developing limb that is responsible for patterning along
the anterior-posterior axis. These cells secrete sonic hedgehog (SHH), a potent
morphogen that directs posterior expansion and patterning (Towers et al.,
2008; Zhu et al., 2008). In the absence of SHH expression, the posterior
zeugopod bones (ulna and fibula) and posterior digits fail to develop (Chiang
et al., 2001; Kraus et al., 2001). In contrast, ectopic anterior expression of
SHH is associated with transformation of anterior zeugopod bone (radius) into
a posterior bone (ulna) and mirror duplication of posterior digits (Riddle et al.,
1993).
In the murine model, Gli3 transcription factor functions as a downstream
effector of Shh signaling. In the absence of Shh signaling, Gli3 is processed
into a truncated repressor variant (Gli3r) (Litingtung et al., 2002). Gli3 is
expressed in the limb bud prior to Shh expression and acts antagonistically to