Congenital Upper Limb Anomalies 169haploinsufficiency, impair limb dorsalization and cause Nail-Patella Syndrome
in humans (Chen et al., 1998).
Coordination of Inter-Axes Patterning
The signaling centers further coordinate patterning during limb outgrowth
by inter-axes regulation. AER-related FGFs and SHH regulate each other in a
positive feedback loop during limb development (Laufer et al., 1994;
Niswander et al., 1994). Loss of FGF signaling from the AER diminishes SHH
expression (Laufer et al., 1994) and removal of SHH downregulates FGF
expression in the AER (Chiang et al., 2001).
SHH regulates FGFs in the AER via Formin, Gremlin, and bone
morphogenic proteins (BMPs). A recessive mutation in mice termed limb
deformity (ld) is characterized by mutations in the Formin locus. Within this
locus resides a cis-regulatory region that negatively affects Gremlin expression
(Zuniga et al., 2004). Gremlin is a BMP antagonist that aids in maintaining the
structural/functional integrity of the AER. In Gremlin-deficient mouse
embryos, a morphologically distinct and functional AER fails to develop
which negatively affects Fgf signaling, and in turn, leads to diminished Shh
expression (Khokha et al., 2003; Michos et al., 2004). Homozygous mice for
the ld mutation present with limb patterning defects characterized by
synostosis of the zeugopod in combination with oligo- and syndactyly of
metacarpal bones and digits (Zeller et al., 1999). Zuniga et al., in their 2004
report, hypothesize that homologous mutations in this cis-regulatory region,
which maps to chromosome 15q13-14 in humans (Maas et al., 1991), may be
linked to human congenital malformations such as Cenani-Lenz-like
nonsyndromic oligosyndactyly which resembles the ld phenotype (Zuniga et
al., 2004).
WNT7a links the dorsal-ventral axis to the anterior-posterior axis by
promoting the expression of SHH (Yang and Niswander, 1995). Similarly, the
loss of Lmx1b function in knockout mice causes a loss in distal ulna formation
in addition to ventral-ventral limbs (Chen et al., 1998). In humans,
homozygous missense mutations of WNT7A causes ulnar deficiency/absence
with loss of one or more ulnar digits in a condition called Al-Awadi/Raas-
Rothschild syndrome (AARRS) (Kantaputra et al., 2010).