Biomedical Engineering Reference
In-Depth Information
uniformly, myofibers become disorganized. These data argue strongly for an
instructive role of Wnt ligands in the PCP pathway. However, it is still ques-
tionable what is the relationship between muscle fiber orientation and PCP,
as polarized localization of core PCP protein, the hallmark of PCP, in
myocytes has not been identified. Furthermore, it is still unclear whether
Wnt11 truly regulates PCP in mammals. Although
Wnt11
/
mutant mice
displayed multiple defects in kidney development and cardiogenesis, no
obvious PCP phenotypes were reported (
Cohen, Miller, Wang, Moon, &
Morrisey, 2012; Flaherty & Dawn, 2008; Majumdar, Vainio, Kispert,
McMahon, & McMahon, 2003; Uysal-Onganer & Kypta, 2012; Zhou
et al., 2007
). In contrast to Wnt5a, Wnt11 does not genetically interact
with core PCP protein, Vangl2 (H. Song & Y. Yang, unpublished data).
Direct evidence that Wnt11 regulates PCP is still lacking.
During development, it is an intriguing question why some of the organs
and tissues preferentially extend in one direction? For instance, the limbs
preferentially elongate along the P-D axis. It was proposed that Fgf (fibro-
blast growth factors) family members secreted from the apical ectodermal
ridge play a central role in limb P-D elongation through setting up a gradient
of proliferation rate (higher at the distal, but lower at the proximal part of
limb buds), which then drives oriented limb elongation along P-D axis
(
Ede & Law, 1969; Fernandez-Teran, Hinchliffe, & Ros, 2006; Hopyan,
Sharpe, & Yang, 2011; Niswander, Tickle, Vogel, Booth, & Martin,
1993; Reiter & Solursh, 1982
). However, elegant experimental and
computational studies based on three-dimensional analysis of developing
limb buds did not support this “proliferation gradient model,” and
suggested directional cell activities, rather than graded proliferation rate,
are the major driving force behind the early limb bud outgrowth (
Boehm
et al., 2010; Gros et al., 2010
). Studies in our lab also showed that when
chondrocytes are forming, they are indeed polarized along the P-D axis,
indicated by asymmetrically localized Vangl2 protein, a hall marker of
PCP. Interestingly, those limb mesenchymal cells that are not
differentiating into chondrocytes in the interdigital region did not show
Vangl2 asymmetrical localization. As Vangl2 asymmetrical localization, as
well as directional outgrowth and extension of cartilage in wild-type
embryo, is abolished in the
Wnt5a
/
mutant, Wnt5a, which is
expressed in the distal limb bud and forms a gradient from distal to
proximal limb, controls elongation of the cartilage along the P-D axis in
limb development through a process that requires PCP (
Gao et al., 2011
).
It is possible that limb mesenchymal cells gain directional information from
