Biomedical Engineering Reference
In-Depth Information
8.4 Cilia-Generated Nodal Flow
Cilia are not only responsible for the motion of cells but they also play an important
role in the development of vertebrates. There are strong experimental indications
that cilia-generated fluid flow is responsible (or at least a necessary requirement)
for the establishment of left and right in developing embryos. We first summarize
the experimental findings supporting this view. In Section 8.4.2 we then give a short
overview of the current theoretical efforts in modeling these observations.
8.4.1 Experimental Facts
Vertebrate development involves three levels of broken symmetry induced by the
specification of three body axes. These events occur at different growth stages par-
titioning the embryo into anterior and posterior (top-bottom), dorsal and ventral
(front-back), and left and right domains [49].
First, the anterior-posterior (A-P) axis of the initially cylindrically symmetric
embryos is determined by newly emerging signaling centers along the future midline
of the embryo [50]. Assuming that the anterior side is randomly selected (as hypoth-
esized in [51]) then L-R symmetry breaking must occur afterwards. This is consistent
with findings that gene expression is transiently symmetric before this stage [52].
The L-R axis must be reliably oriented with respect to A-P and dorso-ventral (D-V)
axes [53].
There is now strong experimental evidence that cilia-generated fluid flow plays an
important (if not essential) role in breaking of left-right symmetry [11, 54, 55, 56].
More precisely, the flow created by monocilia over a small region of the embryo
(node) seems to trigger the establishment of the right and left sides. This node
is a major organizing center regulating pattern formation (see Figure 8.5). During
gastrulation, several genes essential for formation of L-R axis are expressed at or
around the node [57, 58, 59].
As mentioned in the introduction, the monocilia of the ventral node lack the cen-
tral pair of microtubules and thus have a “9 + 0” microtubule arrangement different
from the “9 + 2” arrangements of conventional cilia. They perform a rotation-like
motion, creating a leftward flow over the node [11, 54, 61]. The presence of this
directed flow is necessary for breaking of the L-R symmetry. Experiments by Non-
aka et al. have shown that the absence of functional (motile) monocilia leads to
randomization of the left-right placement of organs [11] (see Figure 8.6). However,
by subjecting the surface of the mouse embryos to an artificial flow (created by a
mechanical pump) L-R patterning was re-established in mice with only non-motile
cilia [62].
The ciliar movement has been analyzed at high temporal resolution [56]. The
nodal monocilia perform a clockwise rotation (if seen from above) around an axis
tilted about
ψ
=40
◦
±
10
◦
to the posterior (where a tilting angle
ψ
=0
◦
corresponds
to an axis normal to the surface), see Figure 8.7. The trajectory described by the
tip of the monocilium is slightly elliptical. Because the velocity field has to vanish
on the surface of the node (i.e., the no-slip boundary condition has to be fulfilled
on the nodal membrane), the cilia induce a larger velocity in the surrounding fluid
during their leftward swing. The rightward swing close to the surface is less effective.
Thus, averaged over one beating pattern, the monocilia effectively push fluid from
the right to the left (see Figure 8.7).
