Congenital Upper Limb Anomalies 165syndrome, which is characterized by abnormalities of the heart and upper
limb, occurs in humans with mutations in the TBX5 gene (Basson et al., 1997;
Li et al., 1997; Mori and Bruneau, 2004). Through loss and gain of function
experiments in chicken and mice, a role for PITX1 in hindlimb specificity has
also been identified (Lanctot et al., 1999; Logan and Tabin, 1999; Szeto et al.,
1999). Misexpression of PITX1 in wing-field of chicks leads to ectopic TBX4
expression and results in hindlimb-specific changes to the limb (Logan and
Tabin, 1999). Pitx1 overexpression in mice and misregulation of PITX1 in
humans (Liebenberg syndrome) lead to similar phenotypes with partial
transformation of the upper limb into a hindlimb (Spielmann et al., 2012; Al-
Qattan et al., 2013; Mennen et al., 2014).
Limb Patterning along the Proximal-Distal Axis (Figure 1C)
Subsequent to limb bud initiation, limb development occurs along three
axes: proximal-distal, anterior-posterior, and dorsal-ventral. Signaling centers
are organized to govern growth and patterning along each axis. The apical
ectodermal ridge (AER) forms as a thickened epithelium at the distal tip of the
limb bud in response to mesodermal signals. FGFs, primarily FGF8 from the
AER, direct growth and patterning along the proximal-distal axis (shoulder to
fingers). A deficiency of Fgf8 and 4 (from the AER) (Boulet et al., 2004) or
Fgf10 (from limb mesoderm) (Min et al., 1998) in mice results in the complete
absence of fore- and hindlimbs. Interrupting AER-related FGF function either
by AER removal in chick wings or conditional Fgf receptor knockouts at
various developmental stages, truncates limbs along the proximal-distal axis
corresponding to its progressive stage of distalization (Saunders, 1948;
Mahmood et al., 1995; Lu et al., 2008; Yu and Ornitz, 2008). In addition,
maintenance of AER integrity and FGF secretion is important for proper digit
formation. Several molecules involved in AER maintenance and FGF8
production have been described including: TP63, DLX5, WNT10B and
FBXW4. Mutations in target genes or regulatory elements associated with this
pathway disrupt AER structure and function, producing a phenotypic spectrum
of abnormalities known as split-hand/foot malformations (SHFM) (Naruse et
al., 2007; Marinic et al., 2013; Restelli et al., 2014; Sowinska-Seidler et al.,
2014).
Activation of FGF-specific intracellular signaling pathways involved in
cell proliferation, growth and differentiation is mediated through FGF binding
to specific receptors (FGFRs) that exhibit tyrosine kinase activity. Abnormal