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First published online January 13, 2009
doi: 10.1242/10.1242/dev.015974
Hypothesis |
1 Center for Regenerative and Developmental Biology, Tufts University, 200
Boston Ave., Suite 4600, Boston, MA 02155, USA.
2 Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA
02155, USA.
* Author for correspondence (michael.levin{at}tufts.edu)
SUMMARY
Consistent left-right (LR) patterning is a clinically important embryonic process. However, key questions remain about the origin of asymmetry and its amplification across cell fields. Planar cell polarity (PCP) solves a similar morphogenetic problem, and although core PCP proteins have yet to be implicated in embryonic LR asymmetry, studies of mutations affecting planar polarity, together with exciting new data in cell and developmental biology, provide a new perspective on LR patterning. Here we propose testable models for the hypothesis that LR asymmetry propagates as a type of PCP that imposes coherent orientation onto cell fields, and that the cue that orients this polarization is a chiral intracellular structure.
Introduction
Internal organs of bilaterally symmetric organisms adopt a consistent
left-right (LR) asymmetry. Errors in this process are of clinical importance
because they cause serious birth defects
(Ramsdell, 2005
). LR
patterning encompasses many of the key themes that fascinate developmental
biologists: the mapping of the same morphogenetic problem and similar
molecular mechanisms upon different embryonic architectures; a patterning
event that cuts across scales of organization; and the linking of epigenetic,
biophysical and transcriptionally mediated mechanisms. This is a particularly
appropriate time for a fresh synthesis of the data on LR patterning because of
diverse recent studies that suggest new ways to understand asymmetry
(Aw et al., 2008;
Danilchik et al., 2006;
Takano et al., 2007;
Xu et al., 2007).
LR patterning accomplishes several logical steps
(Brown and Wolpert, 1990)
(Fig. 1). A midline must be
established, and one side made different from the other. Defects in this
process result in the loss of asymmetry and in changes in organ number and
placement (such as bilateral spleens). LR asymmetry must also become oriented
consistently with respect to the anteroposterior (AP) and dorsoventral (DV)
axes, so that all individuals are consistently asymmetric. The information
needs to be transmitted to multiple organ systems, but midline structures must
perform a restriction function to keep left-sided signals from affecting the
right side, and vice versa. Ultimately, individual primordia carry out
distinct left and right organogenesis programs. Defects in these processes
cause a multitude of LR phenotypes.
The positioning of organs is determined by cascades of asymmetrically
expressed genes (Whitman and Mercola,
2001). Despite exciting recent work on the molecular mechanisms
that lie upstream of asymmetric transcription, the field still faces some
fundamental questions (Aw and Levin,
2008). What is the first event that computes LR orientation? How
are direction and position with respect to the midline communicated from
putative LR-organizing centers and imposed over distant cell fields? How
conserved are the molecular mechanisms involved throughout phyla and do they
reuse modules employed in other morphogenetic events?
The early processes of LR patterning are especially controversial
(Levin and Palmer, 2007;
Tabin, 2005). One view,
motivated by LR randomization observed in mutants of ciliary proteins, holds
that LR asymmetry is initiated by motile cilia beating in the extracellular
space at the node (Fig. 1B)
(Marszalek et al., 1999;
Nonaka et al., 1998;
Supp et al., 1997).
Technologically elegant studies that examined the movement of such cilia
showed that their beating generates a leftward fluid flow
(Kramer-Zucker et al., 2005;
Nonaka et al., 2002;
Schweickert et al., 2007) that
could set up an extracellular morphogen gradient or differential activation of
immotile, mechanosensory cilia (McGrath et
al., 2003). These models are attractive because they demonstrate
how organismal asymmetry could initiate from the molecular structure of cilia,
although there are no data to show that cilia definitively initiate asymmetry
rather than being a downstream step in LR patterning. A key feature of this
class of models is that asymmetry is first determined at gastrulation; another
is that the origin of LR asymmetry is extracellular, as the first detectable
molecular difference between the left and right sides occurs in extracellular
space. Consistent with this hypothesis, motile cilia are necessary for proper
LR patterning in fish, mice and Xenopus
(Bisgrove et al., 2005;
McGrath et al., 2003;
Nonaka et al., 1998;
Okada et al., 1999;
Schweickert et al., 2007).
However, because organisms such as frog, chick, snail, plants and nematodes
develop LR asymmetry prior to, or entirely without, motile cilia
(Spéder et al., 2007;
Levin and Palmer, 2007), this
cannot be the source of LR patterning information in all organisms.
By contrast, a second model, which is motivated by data derived first in
the chick and frog (Levin,
2006), focuses on intracellular events and physiological
mechanisms (Fig. 1A). In
Xenopus, the asymmetric transport machinery within early blastomeres
(Aw et al., 2008;
Qiu et al., 2005) localizes
differential ion channels to the prospective left and right sides of the
embryo (Adams et al., 2006;
Levin et al., 2002;
Morokuma et al., 2008). These
ion transporters then set up physiological gradients that drive the LR
accumulation of morphogens (Esser et al.,
2006; Fukumoto et al.,
2005). The hallmarks of these models are that LR asymmetry is
derived extremely early (long before nodal cilia appear), that asymmetry
originates in the orientation of a cytoplasmic structure, that components of
this system might be very widely conserved, and that intracellular
physiological signals and cell-cell interactions are important in transmitting
LR information across cell fields.
The relative merits of these two models have been discussed in detail
(Levin and Palmer, 2007;
Spéder et al., 2007).
Here, we synthesize several recent findings in cell and developmental biology
and propose a new model based on two independent but compatible hypotheses:
(1) that LR patterning is a kind of planar cell polarity (PCP) that spreads LR
information throughout the embryo; and (2) that the origin of the signal that
orients the coordinated LR planar array is intracellular, operating in single
cells or small groups of cells in which the microtubule cytoskeleton performs
the initial computation to orient polarity. Although many important details
remain to be clarified regarding the mechanisms of LR and PCP patterning, and
although core PCP proteins have yet to be implicated in LR patterning, our
proposal is consistent with recent findings and provides an alternative
mechanism for how symmetry-breaking and orientation steps that first occur in
a small LR coordinator region can be amplified over large cell fields. As our
model awaits direct molecular testing, we also outline several specific
predictions to guide future experimental tests of these ideas.
|
PCP and patterning signal amplification
Tissue function often requires coordinated cell behavior, whether to
achieve directed movement in a plane, as in convergent extension during
gastrulation, or to produce an oriented field of polarized structures, such as
the bristles of the Drosophila wing
(Wang and Nathans, 2007). This
requires directional information to be present in the plane of a cell field
that lies orthogonal to apical-basal polarity. This polarized coordination of
cells in a plane is known as PCP (Fig.
2). The existence of a conserved `core' group of PCP genes that
are crucial in patterning planar-polarized structures in different organisms,
which includes frizzled (fz), dishevelled
(dsh), flamingo (fmi; starry night -
FlyBase) and prickle (pk) in Drosophila
(Axelrod and McNeill, 2002),
suggests that a common mechanism exists for the establishment of PCP
(Seifert and Mlodzik,
2007).
PCP is thought to occur in three steps
(Tree et al., 2002a). First, a
directional cue initiates polarity that orients the field with respect to the
rest of the embryo (Fig. 2A).
The source of this cue is believed to be an extracellular gradient of a
morphogen related to the Wnt family of Fz ligands, although its existence has
not been proven in most instances of PCP. Next, this signal is interpreted by
intracellular factors to produce the asymmetric subcellular localization of
core PCP proteins. These asymmetries then spread across the entire cell field,
perhaps by mutual inhibition and/or stabilization at cell-cell boundaries
(Fig. 2B,C)
(Seifert and Mlodzik, 2007),
creating global parallel arrays of asymmetric intracellular protein
localization. Finally, tissues interpret this subcellular asymmetry during
polarized differentiation and morphogenesis.
We propose that LR patterning is a type of PCP. The field of PCP is a complex one that has several important open questions, including the identity of the initial global directional cue that orients the field with respect to the embryonic axes, the mechanisms by which polarized PCP proteins lead to downstream morphogenetic cascades, and the details of PCP protein interactions in vertebrates. However, the main principles of this important pathway are becoming clear. The PCP system exhibits several crucial properties that might illuminate our understanding of how components important in LR patterning can be coordinated to impose LR directionality.
We propose that PCP and LR patterning can be thought of as being linked at
a number of levels. The broadest comparison between the two is motivated by
the fact that PCP and LR patterning solve the same morphogenetic problem and
share a fundamental logic of patterning control (as described in more detail
below). In addition to the parallels in logic that underlie PCP and LR
patterning, we also highlight similarities in epistatic interactions of PCP
and LR mutants, and intriguing overlaps in the phenotypes of several genetic
mutants. The hypothesis that a deeper, more molecularly conserved link exists
between these two pathways would posit that the spread of LR information could
lie downstream of the same molecular pathways that control classical PCP
readouts, and that perhaps even certain core PCP proteins might themselves
signal in the LR pathway. Although we discuss several genetic mutations that
cause both PCP and LR defects, no published studies have specifically examined
PCP mutants for LR patterning defects. We hope that our proposal spurs such
experiments. However, our hypothesis has relevance aside from any role that
the core PCP genes might have in LR patterning, as PCP may in fact be
patterned by more than one process
(Lawrence et al., 2007). Key
features of PCP patterning in new contexts have led to the definition of PCP
being extended to polarized structures that are patterned by molecules other
than the core group of PCP proteins, such as the dentical structures that line
the Drosophila larval cuticle
(Zallen, 2007). We argue here
that LR patterning is indeed one such context that employs PCP, although
future experiments are required to reveal the degree of conservation of the
molecular players involved.
|
;
Chalmers et al., 2003), as are
the chick (Stern, 1982;
Wei and Mikawa, 2000;
Voiculescu et al., 2007) and
zebrafish (Oteiza et al.,
2008) embryos. Both PCP and LR patterning are processes that
direct the consistent, asymmetric orienting of cells within an epithelium,
orthogonal to two other prespecified axes. To achieve this, cross-talk between
the axes, possibly via the cytoskeleton, is essential
(Djiane et al., 2005;
Li et al., 2008;
Qiu et al., 2005;
Aw et al., 2008). In PCP, key
proteins such as Fz and Strabismus (Stbm; Van Gogh - FlyBase), as discussed
above and shown in Fig. 2, have
first to be recruited to the apical surface in order for planar polarity to
manifest. The proteins are then asymmetrically distributed within the plane of
the cell sheet (Zallen,
2007). Similarly, in Xenopus, the apical-basal axis is
important for the correct establishment of asymmetry, and LR-relevant ion
transporters, such as the H/K-ATPase (see
Table 1), must first reach the
apical blastomere membrane before being asymmetrically plane-polarized in a
similar manner to canonical PCP proteins
(Adams et al., 2006), a process
that is controlled by the chirality of the cytoskeleton
(Adams et al., 2006;
Aw et al., 2008;
Morokuma et al., 2008;
Qiu et al., 2005). It was
recently shown that the four-cell frog embryo is able to integrate information
from its apical-basal and planar polarities to calculate intracellular
directionality (Aw et al.,
2008).
|
). The details of the analogous phenotypes between the
phases of LR and PCP establishment might deviate in other planar-polarized
epithelia. During LR patterning and during PCP establishment in the fly eye,
the coordination of downstream events occurs as a step distinct from the
initial orientation of global polarity with respect to the major embryonic
axes, as signaling to downstream pathways (normally via Nodal in LR
patterning or via fz in PCP) can continue despite the loss of the
upstream global orientation cue. For example, loss of left-right dynein
(Lrd; Dnahc11) (see Table
1) in LR patterning or loss of ds in PCP both result in
random but coordinated asymmetry. Because one would expect loss of the
polarity initiator to lead to loss of polarity, and not to randomized
polarization, this surprising result hints at a similar underlying biophysical
mechanism for PCP and LR patterning.
|
)? Is there a LR coordinator, and, if so, how does
asymmetry information spread? Organisms such as the chick, in which asymmetry
appears to initiate when the blastoderm contains thousands of small cells,
cannot utilize intracellular transport machinery to localize protein cargo to
the left or right sides of the embryo [unlike the process that occurs during
holoblastic cleavage in Xenopus
(Levin, 2006)]. By setting up
an alignment of cellular polarization, PCP could allow intracellular events to
impose polarity on a complete body axis, even in organisms in which each cell
does not span the midline.
It has been suggested that LR information originates locally in a single-
or multiple-cell organizer that first derives the orientation of the LR axis
from the other axes (Aw et al.,
2008; Hyatt and Yost,
1998; Nascone and Mercola,
1997). None of the current models of LR patterning explains how
this information might spread. Interestingly, one model of PCP initiation
offers a possible mechanism: cell-cell interactions via the protein Pk may
establish a polarity between two cells
(Fig. 2B), which can then
spread outwards as a wave of feedback amplification
(Adler, 2002;
Strutt and Strutt, 2002;
Tree et al., 2002b)
(Fig. 2C). Although PCP is
thought of as a tissue-level phenomenon, this model allows PCP to be initiated
cell-autonomously, and indeed small groups of cells can organize PCP
(Adler et al., 2000). Because
proteins involved in LR patterning, such as V-ATPase and H/K-ATPase (see
Table 1), exhibit asymmetric
intracellular localization (Adams et al.,
2006; Levin et al.,
2002; Morokuma et al.,
2008), thereby fulfilling the most fundamental biophysical analogy
between LR patterning and PCP, this model of PCP initiation offers the LR
patterning field a new way of thinking about how asymmetry can propagate.
Another model of PCP holds that each cell in the sheet polarizes
simultaneously in response to a global cue, and that cell-cell interactions
sharpen the alignment. This model might also be compatible with LR
amplification mechanisms because, as argued below and demonstrated clearly by
Xu et al. (Xu et al., 2007),
individual cells might possess an intracellular polarity that can provide
planar (LR) cues and might need a coordination mechanism to synchronize
them.
One of the most attractive features of PCP for understanding LR patterning
throughout phyla is its scale invariance (that is, its applicability to a
field of cells of any size or number), because planar polarity is thought of
as being a global property of tissue structure, which requires asymmetries to
be established in cells located far from each other
(Zallen, 2007). It is
therefore possible that a PCP-like orienting mechanism could provide LR
directional coordination throughout the embryo, regardless of its size or
shape, or even the timing of LR initiation. Because planar orientation in this
class of models is maintained through cell-cell interactions between
neighbors, new cells entering the plane during blastoderm expansion could
derive LR orientation information from their neighbors, and maintain the
orientation of relevant multicellular structures, such as unidirectional gap
junctions (Levin and Mercola,
1999; Zhang et al.,
2003). Although the relevance of PCP in different species remains
to be tested, these models are applicable to diverse body plans, addressing
another key problem in LR patterning today - the degree to which basic
asymmetry mechanisms are conserved across phyla.
Does LR asymmetry originate intracellularly?
Before LR information can be propagated, the LR axis must first be oriented
correctly. Although our hypothesis that LR information spreads by PCP
mechanisms is compatible with many models of initiation, we propose that the
LR axis is first oriented intracellularly, and that the subcellular component
that coordinates the three axes (Brown and
Wolpert, 1990) is a cytoskeletal-organizing center, such as the
centriole or basal body (an organelle derived from the centriole that is found
at the base of cilia).
The early events that set up the Drosophila embryo provide a
well-understood precedent for using ancient, conserved cytoskeletal nucleating
centers, such as centrioles, to set up major body axes
(Steinhauer and Kalderon,
2006). The microtubule-organizing center (MTOC) nucleates
microtubule assembly (Kellogg et al.,
1994) and can position itself in the exact center of even
irregularly shaped cells (McNiven and
Porter, 1988), suggesting that it can integrate the
three-dimensional morphology of the cell. In ciliates, basal bodies have a LR
asymmetry (they are chiral stereoisomers that occur only in one enantiomer),
which is linked to the overall chirality of the cell
(Beisson and Jerka-Dziadosz,
1999; Bell et al.,
2008). Consistent with our hypothesis (as we discuss in more
detail below), LR patterning defects are often seen in patients with
Bardet-Biedl syndrome, a human genetic ciliopathic disorder that leads to
basal body dysfunction (Ansley et al.,
2003; Kim et al.,
2004; Tobin and Beales,
2007).
A cytoskeletal origin of asymmetry is supported by a very interesting
recent study that has shown that the Xenopus egg contains a
pre-existing `East-West' chirality of the actin cytoskeleton wrapped around
the cortex of the egg (Danilchik et al.,
2006). The origin of this chirality is unresolved. As four-cell
Xenopus embryos already exhibit LR asymmetry in protein localization
(Adams et al., 2006), the
counterclockwise cytoskeletal chirality of the egg could be converted into a
LR directionality in the embryo. The sperm entry point, which defines the DV
axis in Xenopus, could select in each embryo a point on the egg's
circumference at which the prior East-West chirality's tangent determines an
orthogonal LR directionality (Fig.
4A-C).
Another significant study for the field of LR asymmetry, in which polarity
in human neutrophil-like differentiated HL60 cells was investigated, recently
revealed that even these non-embryonic cells in culture orient an apparent LR
axis (Xu et al., 2007).
Neutrophils respond to inflammatory stimuli by crawling towards sites of
infection via pseudopods. Strikingly, most cells extended pseudopods to the
left of an imaginary line drawn from the middle of the nucleus towards the
centrosome of each cell (Fig.
4D). This indicates that differentiated HL60 cells appear to have
a functional chirality, with three apparent axes of asymmetry, just as in LR
patterning: that of the imaginary line pointing from the nucleus to the
centrosome (axis 1, geometrically analogous to the embryonic AP axis in LR
patterning); a vertical axis between the coverslip, cell and bathing medium
that is perpendicular to the first axis (axis 2, analogous to the embryonic DV
axis); and a third lateral axis along the surface of the cell along which
biased polarity occurs (axis 3, analogous to the LR axis), in the direction to
the left of the first axis (see Fig.
4D).
Crucially, the HL60 data recapitulate all of the important phenotypes
obtained during manipulation of embryonic LR patterning. Speculating that the
centrosome-related chirality of the cell might be controlled by the cell
division cycle 42 (CDC42)-partitioning defective 6 (PAR6) epithelial polarity
pathway (Cau and Hall, 2005),
Xu et al. (Xu et al., 2007)
examined how disrupting members of the pathway affected cell polarity.
Disruption of the key upstream elements PAR6, CDC42 or phosphotidylinositol
(3,4,5)-triphosphate (PIP3) abolished the neutrophil polarity altogether
(analogous to isomerism in LR patterning, in which organs lose LR asymmetric
morphology or position). The targeting of downstream elements of the pathway,
such as the atypical protein kinase C PKC
(PRKC
) and cytoplasmic
dynein, randomized polarity and abolished the leftward bias of pseudopod
extension (analogous to heterotaxia, in which the position of only some
visceral organs is randomly reversed). Expressing a constitutively active
mutant of GSK3β reversed polarity (analogous to situs inversus, in which
the position of all visceral organs is completely reversed). In both LR
patterning and neutrophil polarity, a Wnt pathway regulator fully reverses the
asymmetry and causes cells to polarize to the right; in the case of HL60
cells, this is the constitutively active GSK3β, whereas in the case of
vertebrate asymmetry it is a mutant of the inversin (Inv; Invs) protein
(Morgan et al., 1998) (see
Table 1). As in LR asymmetry,
the leftward bias of the HL60 cells was shown to require microtubule
organization and the dynein motor (Aw et
al., 2008; Supp et al.,
1999).
|
These data are consistent with our proposal that cytoskeleton-dependent
intracellular trafficking has a role in aligning a major axis of polarity (in
both PCP and the LR axis). For example, in the fly wing epithelium, Fz protein
is transported through the cells by an oriented cytoskeletal array
(Shimada et al., 2006). This
is precisely what occurs in LR patterning in at least some other species
(Aw et al., 2008). Both PCP and
LR asymmetry may use the cytoskeleton as a vector for orienting key polarized
molecules within cells.
Overlapping PCP and LR phenotypes in ciliary mutants: a shared underlying cause?
Whether mutations in core PCP genes cause LR randomization has yet to be directly tested. Interestingly, as we discuss below, mutations in several genes involved in basal body/ciliary function (see Table 1) cause specific LR defects and the mispatterning of planar-patterned epithelia, suggesting that a common mechanism underlies epithelial PCP and LR patterning.
The inversin gene is partially deleted in Inv/Inv mice, inducing
100% organ inversion (Mochizuki et
al., 1998; Morgan et al.,
1998). Inv RNA is transcribed from the two-cell stage
(Eley et al., 2004;
Nurnberger et al., 2006), and
its protein exhibits a dynamic distribution in both ciliated and non-ciliated
cells: at different parts of the cell cycle, it localizes to basal bodies,
primary cilia, cell-cell junctions, plasma membrane, polarized microtubule
pools [where it interacts directly with tubulin and N-cadherin in the
cytoplasm (Nurnberger et al.,
2002)] and the spindle poles
(Eley et al., 2004;
Nurnberger et al., 2002;
Nurnberger et al., 2004). Of
note, inversin also localizes to the mother centriole (and not the daughter
centriole) of cells even before the primary cilium extends
(Watanabe et al., 2003). This
finding is particularly interesting because the daughter centriole takes its
cues from, and is always formed at right angles to, the mother centriole,
which provides spatial patterning and orientation information to organelles
such as the nucleus (Feldman et al.,
2007). Interestingly, Inv mutant mice exhibit hair
pattern changes that resemble those seen in frizzled 6
(Fzd6)-deficient mice, and Inv was recently shown to act as a
molecular switch between canonical and non-canonical (PCP) Wnt signaling
pathways. In transfected cells, Inv localizes to, and directly binds, PCP
proteins such as Stbm and Pk, and interacts and colocalizes with Dsh. Inv
protein inhibits canonical Wnt signaling by targeting cytoplasmic Dsh for
degradation; it is also required in PCP-dependent gastrulation movements in
Xenopus (Simons et al.,
2005). Some of the inv loss-of-function phenotypes in
zebrafish can be rescued by diversin (ankyrin repeat domain
6 - ZFIN), which exhibits homology to the Drosophila PCP gene
diego (Moeller et al.,
2006; Schwarz-Romond et al.,
2002).
Polaris (Ift88) loss-of-function in mouse and zebrafish
also results in LR patterning defects
(Bisgrove et al., 2005;
Moyer et al., 1994;
Murcia et al., 2000;
Schrick et al., 1995;
Taulman et al., 2001).
Polaris encodes a protein that localizes to cilia and basal bodies.
It functions in intraflagellar transport and remains associated with the
centrosome in non-ciliated cells (Robert
et al., 2007). Polaris interacts genetically with the PCP
gene Vangl2 (Jones et al.,
2008), and Polaris inactivation in mice leads to
misoriented stereociliary bundles in the organ of Corti, similar to the
phenotype seen in mouse embryos with mutations in Vangl2 and in
another PCP gene, Fzd3. In Polaris mutants, the position of
misoriented stereociliary bundles strongly correlates with that of the
mislocalized basal bodies, consistent with Polaris and the basal body
being intracellular sources of polarization information in both LR asymmetry
and PCP.
Bardet-Biedl syndrome (BBS) is a pleiotropic human genetic disorder in
which LR randomization features. Twelve BBS genes have been identified, and
most play roles in intracellular trafficking and in basal body and cilia
function (Ansley et al., 2003;
Kim et al., 2004;
Tobin and Beales, 2007). Among
the BBS genes, Bbs4 mouse mutants exhibit classical PCP phenotypes,
such as neural tube defects and disrupted cochlea stereociliary bundles
(Ross et al., 2005). Bbs1,
Bbs4 and Bbs6 interact genetically with the PCP gene
Vangl2 in both mouse and zebrafish, further supporting a mechanistic
link between basal body/cytoskeleton, intracellular trafficking, PCP and LR
asymmetry. BBS mutant mice do not exhibit situs inversus, but occasionally do
exhibit multiple accessory spleens (P. Beales, personal communication).
Nephronophthisis (NPH) is an autosomal recessive kidney disease.
Loss-of-function of Inv or nephrocystin 3 [nephronophthisis 3
(Nphp3)] leads to situs inversus in mice
(Bergmann et al., 2008). Nphp3
directly interacts with Inv, and both can inhibit canonical
(β-catenin-dependent) Wnt signaling
(Bergmann et al., 2008;
Simons et al., 2005). Loss of
NPHP3 function in Xenopus leads to defects in PCP-dependent processes
such as convergent extension and neural tube closure
(Bergmann et al., 2008).
| Box 1. Models for how PCP and LR patterning might interact in ciliary
mutants
Ciliary beating is a sensitive readout of the polarity of a cell
(Boisvieux-Ulrich and Sandoz,
1991 There are other possible explanations for the LR and PCP phenotypes in ciliary mutants. Cilia may be important in patterning PCP. However, because non-ciliated epithelia also exhibit PCP, for this to hold, PCP mechanisms would have to have evolved separately in ciliated and non-ciliated epithelia. It is also possible that the roles of ciliary proteins in PCP and LR patterning are different and arose independently. However, because the logical structures of the two phenomena are similar, and, in animals such as the chick, LR begins to be patterned in epithelia that already have PCP proteins at work, it seems plausible that the cell's polarity machinery was co-opted to solve the two problems via the same mechanism, instead of functionally buffering them from each other.
|
The phenotypes of these genetic mutants reveal consistent links between
basal body/ciliary function, PCP and LR patterning. One possibility is that
ciliary defects underlie both the LR and PCP phenotypes. However, the ability
of many non-ciliated tissues to achieve PCP, and a lack of obvious primary
cilia defects in LR mutants that carry mutations in genes expressed in ciliary
cells that have ciliary functions, such as in seahorse (leucine
rich repeat containing 6 - ZFIN) (see
Table 1) and Inv
(Kishimoto et al., 2008;
Watanabe et al., 2003), lead
us to propose that ciliary dysfunction and LR defects might both be parallel,
downstream consequences of impaired planar polarity (see
Box 1).
PCP as an amplifier of intracellular LR information: model predictions
A fundamental prediction of our model is that LR information propagates by
the polar localization of protein complexes within cells in epithelia. Such
subcellular asymmetries (of ion transporter proteins, for example) do indeed
exist in embryonic epithelia undergoing LR patterning
(Adams et al., 2006;
Levin et al., 2002;
Morokuma et al., 2008). This
model also predicts the reversal of LR patterning that results from the
surgical rotation of the blastocoel roof in Xenopus embryos
(Mangold, 1921;
Yost, 1992). It remains to be
tested whether the localization of LR components is driven by the same
mechanism that establishes polar localization of core PCP proteins.
As discussed above, LR and PCP defects both result from the disruption of
key intracellular proteins, as predicted by our model. That these defects are
specific, occurring in otherwise largely normal embryos, suggests that the
concordance of LR and PCP phenotypes is not due to the interruption of basic
housekeeping pathways that are important for other patterning events. Our
hypothesis of a link between the canonical planar polarity of various
embryonic structures and LR patterning is also consistent with the recently
revealed role of PCP in determining hair whorl patterns
(Guo et al., 2004;
Wang et al., 2006). Our model
predicts the formerly mysterious relationship between the direction of hair
whorls on the scalp and the mirroring of subtle structures in monozygotic
twins (Jansen et al., 2007;
Levin, 1999;
Weber et al., 2006).
|
), for PCP in the Drosophila wing
(Adler et al., 2000), and even
in single cells in culture (Xu et al.,
2007). Many details of this process are still unclear, including
the mechanistic models of cytoskeleton-organizing centers and the basal body
proteins. It also remains to be seen whether an intracellular orienting cue
will be uncovered in canonical examples of PCP.
This model also makes another key prediction that distinguishes it from
ciliary models of LR initiation: asymmetry phenotypes in non-conjoined
monozygotic twins (Fig. 5). If
LR-relevant polar localization events occur very early, twins produced by
blastomere separation will exhibit some incidence of reversal of asymmetry. By
contrast, if LR is initiated by nodal cilia, asymmetry should be 100% normal
in early-split twins as no LR information would have been derived before the
split, and the cilia will beat in the normal direction in each twin during
gastrulation. Indeed, the literature contains numerous unexplained examples of
book-ending (mirror imaging of unilateral defects and asymmetric traits) in
monozygotic twins (reviewed by Levin,
1999; Levin,
2001), including opposite sidedness of facial defects. Book-ending
in monozygotic twins lends support for an intracellular, chiral origin of
asymmetry. The conservation of chirality within a pair of splitting cells has
been beautifully illustrated by Albrecht-Buehler, who showed that after
division, daughters of mammalian cells in culture have mirror-image
cytoskeletal organization and subsequent migration trajectories
(Albrecht-Buehler, 1977).
Interestingly, the mirroring of daughter cells was not completely penetrant,
providing a testable quantitative prediction for the incidence of book-ending
in monozygotic twins. These data suggest that the initial chiral orientation
is disrupted by early cleavage, but that subsequent amplification proceeds
normally if the initial polarizing cue is reversed. Newt embryos separated at
the two-cell stage also exhibit an 89% incidence of organ laterality reversal
in one of the twins (Takano et al.,
2007), despite being normal with respect to other morphogenetic
events. Thus, the LR axis must have already been orientated by the time of
splitting. The twinning data do not therefore support the late-origin ciliary
models, but are straightforward predictions of early, intracellular chirality
mechanisms.
Limitations and experimental tests of the model
Do our models fit all of the data? Although we favor an early intracellular
origin for the initial alignment of the LR axis, such as a MTOC, known to be
crucial for planar polarity (Jones et al.,
2008; Nubler-Jung et al.,
1987), the amplification aspect of a PCP model is equally
compatible with signals being generated by a later organizer, such as the
ciliated node. Thus, the origin phase and the amplification phase are
independent features of our model.
Although it is clear that, at least in some species, LR components are
plane-polarized in epithelia, there is currently a dearth of functional data
that directly tests the relationship between core PCP proteins and LR
patterning. The PCP gene flamingo is LR asymmetrically expressed in chick
embryos (Formstone and Mason,
2005); this is not obviously predicted by our model, although
flamingo protein localization has not been examined at the cell level in
chick. Canonical PCP genes are expressed in the mouse embryo during streak
elongation (Crompton et al.,
2007), but dissection of PCP from ciliary mechanisms by
conditional gene inactivation remains to be performed in mammalian LR mutants.
Likewise, the roles, if any, of the physiological LR signals, such as the
movement of ions and serotonin (Levin,
2006; Raya et al.,
2004), in PCP have not yet been examined.
Several studies have described the occurrence of PCP defects in the absence
of LR randomization, and vice versa
(Montcouquiol et al., 2003;
Pennekamp et al., 2002).
However, the independent occurrence of these phenotypes does not strictly
contradict our models because the pathways could utilize similar molecules at
one point in the pathway but different ones at others (the pathways could use
the same logic but at some point diverge). However, it should be noted that
PCP and LR defects can be far from obvious if not specifically looked for in
embryos. It is possible that organ of Corti polarization defects might have
been missed in LR mutant mice, and the incorrect coiling of the reproductive
system, a subtle LR defect (Coutelis et
al., 2008), might have easily been missed in the analyses of
canonical Drosophila PCP mutants. Furthermore, fly PCP mutants are
often genetic mosaics created specifically to examine PCP in the eye or wing;
more spatially extensive gene inactivation might be required to elucidate the
roles, if any, of PCP proteins in LR patterning
Our model does not constrain additional important questions in the LR
field, such as how LR direction is converted into position with respect to the
midline, or whether the final positional readout available to organ primordia
contains a range of values along the LR axis or only binary right-versus-left
information. Many questions as to the details of cytoskeletal orientation in
both PCP and LR patterning remain. Our model predicts that, as in LR
patterning, certain kinds of mutations of intracellular proteins should alter
the orientation of a properly patterned epithelium with respect to the rest of
the embryo. For example, there might exist mutants that cause specific
reversals of PCP with respect to body axes (rather than loss of coordination),
but to our knowledge this has been observed very rarely and to a limited
extent only in the Drosophila wing, where regions of reversed
polarity have been seen in dachsous mutants
(Adler et al., 1998), and in
the eye (Simon, 2004). Such
phenotypes have not yet been reported in vertebrates. Expression of the
Inv mutant gene, which may not be a true null, in Drosophila
might reveal a novel PCP phenotype, and such phenotypes should be carefully
looked for in both flies and mammals to test our model and to identify
upstream orientation signals.
The epithelium of the chick embryo blastoderm is an ideal model in which to
look for the interaction of PCP components with early markers of LR asymmetry,
such as the left-sided depolarization of cells during streak initiation
(Levin et al., 2002). Both
vertebrate and invertebrate models of PCP could be used to probe for
biochemical and genetic interactions between canonical planar polarity
proteins and H+ pumps and K+ channels. We are currently
directly testing the PCP model by examining PCP-relevant proteins for LR
asymmetrical localization in cells of chick and frog embryos, and testing
specific disruptors of PCP for their ability to randomize embryonic LR
patterning. Planar-polarized gradients of pH, Ca2+ fluxes and
membrane voltage at the level of individual cells should be looked for in
chick, frog, mouse and zebrafish epithelia at early stages of LR
patterning.
Conclusion
Subtle intracellular asymmetries are revealed by the consistently polarized
pseudopodia in human HL60 cells, the mirror image paths of daughter mouse 3T3
cells (Albrecht-Buehler, 1977),
and by the mirror asymmetry in monozygotic twins of mammals and amphibia. Our
hypothesis suggests that LR asymmetry derives from a cellular chirality that
exists in single cells; it is directly apparent in the handed chirality of
protozoa, but must be amplified in multicellular species. PCP, which is a
conserved and powerful patterning system that solves fundamentally the same
morphogenetic problems as those faced by LR asymmetry, is an ideal mechanism
for imposing LR signals over large fields of cells.
Our basic hypothesis holds that two predefined axes allow the chiral
cytoskeleton to initiate the asymmetric (polarized) intracellular localization
of LR machinery. This is supported by existing data and it is plausible that
if single cells already have the components necessary to drive and amplify
cytoskeletal asymmetry (Aw et al.,
2008; Levin,
2006), this toolkit might be reused for asymmetry in diverging
multicellular lineages. A number of mutations in basal body/ciliary proteins
result in both laterality and PCP phenotypes, and PCP provides a conceptually
satisfying system for LR patterning across different scales. However, our
proposal that a deeper molecular link exists between LR patterning and PCP
remains to be tested, as core PCP proteins have not been linked to the LR
pathway and no data yet identify an intracellular molecule in the large-scale
orientation of PCP fields. Synthetic in silico modeling at multiple levels of
organization coupled with a molecular investigation of the parallels between
PCP and LR patterning should test our hypotheses and might reveal fascinating
new aspects of developmental and cell biology.
Footnotes
We thank Jennifer Zallen, Janine Beisson, Cliff Tabin, Ann Ramsdell, Chris McManus, Stephane Noselli, Ying Zhang and members of the Levin laboratory for many useful discussions. The authors are supported by the March of Dimes, American Heart Association and NIH (M.L.), and by the Agency for Science, Technology, and Research, Singapore (S.A.). Deposited in PMC for release after 12 months.
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