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First published online 15 September 2004
doi: 10.1242/dev.01389
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1 Division of Mammalian Development, National Institute for Medical Research,
The Ridgeway, Mill Hill, London NW7 1AA, UK
2 Division of Developmental Biology, National Institute for Medical Research,
The Ridgeway, Mill Hill, London NW7 1AA, UK
** Author for correspondence (e-mail: a.rana{at}gurdon.cam.ac.uk)
Accepted 23 July 2004
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SUMMARY |
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TOP
SUMMARY
Introduction
Materials and methods
Results
Discussion
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Key words: D2LIC, Axis formation, Handedness, Mouse embryo, Intra-flagellar transport, Lefty2, Hnf3ß
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Introduction |
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SUMMARY
Introduction
Materials and methods
Results
Discussion
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). The
dynein family has been divided into two subfamilies: the axonemal and
cytoplasmic dyneins. Axonemal dyneins function as structural elements in cilia
and flagella, and provide the force responsible for ciliary motion. By
contrast, cytoplasmic dyneins are motor proteins involved in the intracellular
transport of cargo along microtubules and in retrograde intraflagellar
transport during the assembly of cilia
(Perrone et al., 2003).
The dyneins have been implicated in many cellular and developmental
processes. For example, the gene responsible for the spontaneous classical
mouse mutation inversus viscerum (iv) is an axonemal heavy
chain dynein named left-right dynein (previously lrd;
Dnahc11 – Mouse Genome Informatics)
(Supp et al., 1997).
Dnahc11 is expressed in the node of the mouse embryo and is necessary
for the motility of cilia in the node. It is required for the establishment of
the left-right body axis and has been implicated in Kartagener's and other
immotile cilia syndromes (Supp et al.,
1997). In addition, dyneins have been associated with severe
clinical abnormalities, such as heterotaxia and isomerism (including
polysplenia or asplenia), and with single organ inversions, such as
dextrocardia (Casey and Hackett,
2000), as well as in human genetic disease syndromes including
spinal bulbar muscular atrophy and spinal muscular atrophy
(Hafezparast et al.,
2003).
The importance of intra-flagellar transport in embryonic development has
been emphasised by analysis of wimple (previously Wim; Ift172 – Mouse
Genome Informatics) and flexo (previously Fxo; Tg737Rpw – Mouse Genome
Informatics) (Huangfu et al.,
2003), which, together with the kinesin Kif3a
(Marszalek et al., 1999;
Takeda et al., 1999), are
involved in anterograde intra-flagellar transport. Mouse mutants lacking
Wim or Fxo fail to specify ventral cell fates, probably
because Shh signalling is disrupted downstream of the patched receptor
(Huangfu et al., 2003).
Together, these observations emphasise that the study of dyneins is of
great cellular, developmental and medical interest. Recently, on the basis of
its amino acid sequence and its ability to interact with cytoplasmic dynein 2
heavy chain (DHC2), Grissom and colleagues
(Grissom et al., 2002) have
classified dynein 2 light intermediate chain (D2LIC) as a novel member of the
dynein family of proteins. Consistent with this proposal, XBX-1, the
Caenorhabditis elegans homologue of D2LIC, proves to be required for
retrograde intraflagellar transport
(Schafer et al., 2003). We
previously identified mouse D2LIC (mD2LIC; 4933404O11Rik
– Mouse Genome Informatics) as a gene that is expressed in the node of
the developing embryo (Sousa-Nunes et al.,
2003), and in this paper we investigate its function during
development. Our work shows that mD2LIC is needed to maintain or
establish ventral cell fates, for monocilium formation in the ventral node,
and for correct signalling by the organiser and midline. Our experiments
define the first embryonic function for a vertebrate cytoplasmic dynein.
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Materials and methods |
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SUMMARY
Introduction
Materials and methods
Results
Discussion
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)
using probes derived from EST clone AL024282. Probes specific for other genes
are described in the text. The lefty probe
(Meno et al., 1997) detects
both Leftb (previously lefty1) and Ebaf (previously
lefty2) transcripts.
Northern blot analysis
Total RNA was isolated from adult tissues and from 11.5 dpc whole embryos
and placenta as described (Chomczynski and
Sacchi, 1987). A probe was prepared from a full-length
mD2LIC cDNA. Hybridisation was performed as described
(Martinez-Barbera et al.,
1997).
Scanning electron microscopy
Scanning electron microscopy was performed as described
(Sulik et al., 1994), with 15
minutes uranyl acetate treatment.
TUNEL staining
TUNEL staining was performed as described
(Barbera et al., 2002).
Gene targeting
Genomic clones were isolated from a 129/Olac genomic library (Stratagene)
using an mD2LIC full-length cDNA to generate a probe. A 2.75 kb
region of the endogenous genomic locus was replaced by homologous
recombination in E14TG2A ES cells with a 2 kb loxP flanked PGK
neomycin (PGKneo) cassette using a diphtheria toxin A
(DTA) cassette for negative selection
(Fig. 3). Correctly targeted
cells from five independent cell lines were used to generate chimeric animals
that were subsequently mated to produce heterozygous individuals. Only
heterozygotes derived from the same cell line were intercrossed. The
phenotypes of homozygous individuals derived from each of the five cell lines
were similar, indicating that the embryonic defects observed in this paper are
consequences of the targeting event.
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Results |
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TOP
SUMMARY
Introduction
Materials and methods
Results
Discussion
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), we
find that mD2LIC protein is predicted to contain 351 amino acids, with a
putative P-loop (nucleotide binding domain) near its N terminus
(Fig. 1). We believe that this
discrepancy has arisen because Grissom and colleagues
(Grissom et al., 2002) made
use of an EST sequence (mouse locus AK008822, BAB25915; M. musculus
Genome Sequencing Consortium) that contains a frame shift relative to the
sequence presented in our study; when translated, this results in a 209 amino
acid protein that lacks the P-loop domain. Our translation of the
mD2LIC cDNA (Sousa-Nunes et al.,
2003) yields a protein that closely resembles the 350 amino acid
human D2LIC, such that there is 87% identity and 92% amino acid charge matches
between the two proteins.
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)
(Fig. 2A-E). Northern blot
analysis reveals a single transcript of 1.4 kb, and in the adult strongest
expression of mD2LIC occurs in kidney and brain
(Fig. 2F). The initial
expression pattern of mD2LIC resembles that of the axonemal
left-right dynein (lrd), suggesting that mD2LIC,
like lrd, is involved in establishment of the embryonic axis
(Supp et al., 1999).
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;
Crossley and Martin, 1995;
Echelard et al., 1993;
Wilkinson et al., 1990). At
the late streak stage, expression of Fgf8 is normal in null mutant
embryos (Fig. 5A,B), while
expression of both Shh (n=5/5;
Fig. 5C-E) and T
(n=5/5; data not shown) is slightly reduced. Most significantly,
expression of Foxa2 in the region of the node was severely reduced in
mD2LIC–/– embryos (n=7/9), and in
some was almost undetectable (n=2/9)
(Fig. 5F-J).
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;
Kitamura et al., 1999;
Meno et al., 1997).
Nodal is the earliest known asymmetric marker of the left-right axis.
In wild-type embryos expression first occurs symmetrically around the
periphery of the node, but it then becomes asymmetrical, with higher levels
and a broader domain of expression on the left-hand side. nodal is
then also expressed in the left-hand lateral plate. At late streak stages
nodal expression was reduced in three
mD2LIC–/– embryos, was absent in one, and, in
contrast to its normal expression pattern, was expressed symmetrically around
the node in eight (Fig. 6G,H
and data not shown). At later stages (2-5 somite stages), left-sided
(n=2/9), right-sided (n=1/9) and bilateral (n=5/9)
expression patterns were observed in the lateral plate, and in one embryo
(n=1/9) no expression was detectable. We note that the frequency of
bilateral expression is similar to the frequency of the more severe Class I
and II mutants (Table 2).
Expression of Leftb was undetectable in all null embryos
(n=5/5), while Ebaf expression occurred bilaterally in three
out of five embryos, was expressed on the right-hand side in another, and was
absent in a fifth (Fig. 6L,M). Similar results were observed with Pitx2
(Fig. 6N-Q). Together, these
results indicate that left-right asymmetry is not generated correctly in
mD2LIC–/– embryos, perhaps owing to the
impairment of ciliogenesis and subsequent disruption of Nodal signalling,
together with impaired development of the midline (see Discussion).
Anterior truncations and neural tube closure defects in mD2LIC–/– mutants
The later phenotypes observed in mD2LIC null embryos, such as
anterior truncations and defects in neural tube closure, are likely to be
consequences of the earlier defects. For example, expression of Foxa2
in the anterior definitive endoderm of
mD2LIC–/– mutants is greatly reduced
(Fig. 5I,J), and this is
accompanied by extensive cell death in this tissue
(Fig. 5K-P). mD2LIC is
not normally expressed in the anterior definitive endoderm, suggesting that
these cells are deprived of a survival signal that is normally produced by the
node or its derivatives. During normal development, the anterior definitive
endoderm maintains an Fgf8 signalling centre in the anterior neural
ridge, which in turn is required for correct anterior development
(Martinez Barbera et al.,
2000; Shimamura and
Rubenstein, 1997). Fgf8 expression in the anterior neural
ridge is significantly reduced in mD2LIC–/–
mutants (Fig. 6R,S), presumably
because of defects in the anterior definitive endoderm, and the decrease in
Fgf8 will lead to defects in anterior development
(Fig. 7).
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; Huangfu et al.,
2003; Wallingford and Harland,
2002) and modelling of the dorsal neural tube through apoptosis
(Martinez Barbera et al.,
2000); the process also requires mechanical support from adjacent
cephalic mesenchyme (Weil et al.,
1997). All these steps are likely to be affected in
mD2LIC–/– embryos. Perhaps most significantly,
reduced expression of Shh will prevent the notochord from acting as a
normal signalling centre, thereby interfering with formation of the floorplate
and with expression of Foxa2, Shh and Ebaf. In addition,
however, TUNEL analysis at 9.0-9.5 dpc reveals that
mD2LIC–/– embryos exhibit reduced levels of
cell death in the hindbrain and also that there is ectopic cell death in the
cephalic mesenchyme (Fig.
6T-Y). The elevated levels of apoptosis in the latter tissue may
deprive the closing neural tube of its required mechanical support. These and other aspects of the mD2LIC–/– phenotype are summarised in Fig. 7 and discussed below.
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Discussion |
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SUMMARY
Introduction
Materials and methods
Results
Discussion
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;
Morris and Scholey, 1997). The
particles are conveyed back to the base of the cilium by retrograde transport,
and as we discuss below, it is this process that requires cytoplasmic dyneins
such as mD2LIC.
Evidence implicating cytoplasmic dyneins in retrograde transport comes from
work in Chlamydomonas and Caenorhabditis elegans.
Chlamydomonas lacking either dynein 2 heavy chain (DHC2) or dynein light
chain (LC8) fail to undergo normal ciliogenesis, and any cilium-like
structures that do form are reabsorbed
(Pazour et al., 1999;
Pazour et al., 1998). mD2LIC
can associate with DHC2 (Grissom et al.,
2002; Perrone et al.,
2003), suggesting that this cytoplasmic dynein is also involved in
retrograde transport. Consistent with this idea, ciliogenesis is impaired in
C. elegans lacking XBX-1, a homologue of D2LIC, and as in the
Chlamydomonas mutants, those cilia that do form subsequently
disappear, perhaps through reabsorption
(Schafer et al., 2003).
Together, these results suggest that loss of mD2LIC in the mouse node is
directly responsible for the observed defects in cilium formation.
How does defective ciliogenesis lead to the mD2LIC–/– phenotype?
As discussed below, several aspects of the mD2LIC mutant phenotype
may be due directly to the loss of cilia and a disruption of nodal flow. Other
defects, however, such as the early downregulation of genes such as
Foxa2 and Shh, may have a more indirect aetiology. There
may, for example, be a general impairment of cellular function: D2LIC is
present in the Golgi apparatus and centrosomes
(Grissom et al., 2002), and
its loss may cause defects in protein maturation, in the cytoskeleton or in
cell polarity.
Other elements of the mD2LIC–/– phenotype
may result from a reduction in Hedgehog activity. The more severely affected
mD2LIC–/– embryos resemble those deficient in
Hedgehog signalling, such as the Smo–/– single
mutant and
Shh–/–/Ihh–/–
double mutants (Zhang et al.,
2001). mD2LIC–/– individuals also
resemble embryos lacking nt, rotatin or Sil, as well as
chimeric and conditional Foxa2–/– embryos
(Dufort et al., 1998;
Faisst et al., 2002;
Hallonet et al., 2002;
Izraeli et al., 1999;
Melloy et al., 1998). Like
mD2LIC–/– embryos, many of these mutants lack
midline expression of Foxa2, one consequence of which would be a
downregulation of Shh (Filosa et
al., 1997).
It is possible that some of the later elements of the
mD2LIC–/– phenotype are also consequences of
defects in the Hedgehog signal transduction pathway. The phenotypes of our
least severe `Class III' embryos resemble those of embryos lacking the
intra-flagellar transport proteins Kif3a, Wim, Polaris and Fxo, in all of
which the neural tube fails to close in the region of the head
(Huangfu et al., 2003;
Takeda et al., 1999). This is
a characteristic of embryos that lack Shh
(Huangfu et al., 2003) and it
is possible that mD2LIC–/– individuals, such
as Wim–/–,
Polaris–/– and
Fxo–/– embryos, are defective in Shh signal
transduction as well as in Shh expression.
Finally, and as mentioned above, the lack of nodal cilia in
mD2LIC–/– mice would be expected to interfere
with nodal flow, and therefore with specification of the left-right axis. In
the nodal flow hypothesis (Nonaka et al.,
1998), cilia have been suggested to cause the unidirectional flow
of a morphogen that thereby accumulates on just one side of the node and
activates gene expression in an asymmetric fashion. More complicated models
involve two populations of node monocilia, in which one population generates a
fluid flow and the other senses and transduces it, thereby leading to an
asymmetric calcium signal at the left-hand-side of the node
(McGrath et al., 2003;
Tabin and Vogan, 2003).
The absence of nodal cilia would disrupt asymmetric gene expression and
thereby set in train the series of events that cause the defects we observe in
mD2LIC–/– embryos. These events are described
in Fig. 7, and include the
decreased or symmetrical expression of genes such as Nodal, as well
as the downregulation of T, Foxa2 and Shh. They culminate in
the requirement for mD2LIC in the survival of the anterior definitive
endoderm and thereby for maintenance of the anterior neural ridge and for
normal anterior development. Models involving maintenance of the anterior
neural ridge by anterior definitive endoderm have been proposed previously
(Camus et al., 2000;
Hallonet et al., 2002),
although this is the first time that defects in axial mesendoderm have been
shown to lead to cell death in the anterior definitive endoderm.
Regulation of mD2LIC
Recent work has demonstrated that expression of mD2LIC is
downregulated in Rfx3-deficient mouse embryos, and that these embryos too show
defects in cilium development and left-right axis specification
(Bonnafe et al., 2004).
Expression of mD2LIC is not completely absent in
Rfx3–/– individuals, however, and the
phenotype of such mice is not as severe as that of our mD2LIC
mutants, suggesting that other proteins also regulate mD2LIC
expression.
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ACKNOWLEDGMENTS |
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Footnotes |
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Present address: Neural Development Unit, Institute of Child Health, 30
Guilford Street, London, WC1N 1EH, UK
Present address: MRC Clinical Sciences Centre, Faculty of Medicine,
Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London,
W12 0NN, UK
Present address: Developmental Biology Program, Victor Chang Cardiac
Research Institute, 384 Victoria Street, Darlinghurst, NSW 2010, Australia
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TOP
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Introduction
Materials and methods
Results
Discussion
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