Medical University of South Carolina, Department of Cell Biology, 171 Ashley Avenue, Charleston, SC 29425-2204, USA
* Author for correspondence (e-mail: argraves{at}musc.edu)
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Summary |
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Key words: Hedgehog, Retinol, Retinoic acid, Endocytosis, Transcytosis, Holoprosencephaly
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Introduction |
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Megalin expression in development |
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Megalin and regulation of retinol-dependent development |
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With respect to the first possibility, megalin would be expected to be
expressed by cells that also express retinaldehyde dehydrogenases (Raldh),
enzymes that oxidize retinal to RA. However, there is evidence that this is
not the case. In the mouse, there are three Raldh genes,
Raldh1-Raldh3. The pattern of cells in the developing mouse embryo
that express Raldh1-3 (Mic et al.,
2002) does not closely overlap with that of megalin expression
(Kounnas et al., 1994
). Raldh1
is expressed in the ectoderm of the dorsal retina of the eye (E10.5)
(Mic et al., 2002
) and the
substantia nigra of the developing brain (E15.5)
(Smith et al., 2001
). Raldh2
is highly expressed in the mesoderm of the trunk region of murine embryos
(E8-E9) but absent in the developing brain
(Smith et al., 2001
). Smith et
al. have proposed that RA produced by this trunk mesoderm diffuses both
dorsally and medially to developing hindbrain tissue
(Smith et al., 2001
). Raldh3
is expressed in surface ectoderm of the optic vesicle (9-10.5 dpc)
(Mic et al., 2002
;
Smith et al., 2001
). In
contrast to these patterns of Raldh gene expression, megalin is initially
expressed in the floor plate and along apical margins of the neural tube
(McCarthy et al., 2002
) and
later in the choroid plexus and ependymal layer of the brain
(Kounnas et al., 1994
). The
fact that megalin and the known Raldh genes do not seem to be
expressed in the same tissues argues against megalin playing a role as a
mediator of retinol uptake by cells that synthesize RA. However, a recent
study in which Raldh2-deficient embryos were conditionally rescued shows sites
of RA synthesis that do not correspond to sites of expression of the known
Raldh genes (Mic et al.,
2002
) but show some overlap with sites of megalin expression. For
example, novel sites of RA synthesis include the floorplate and neural tube,
which are known to also express megalin
(McCarthy et al., 2002
).
Therefore, the possibility that megalin mediates uptake of retinol by a subset
of RA-synthesizing cells, particularly neural epithelial cells, must still be
considered.
If megalin plays a role in transport of retinol to cells that synthesize
RA, there are two possibilities: one, megalin expressed by extraembryonic
visceral endoderm (VE) mediates transport of maternally derived retinol to the
embryo; and two, megalin expressed on apical surfaces of certain embryonic
epithelia mediates transepithelial transport of retinol to centers of active
RA biosynthesis. If the first possibility was correct, megalin-deficient
embryos would display a phenotype consistent with a retinol deficiency.
However, embryos lacking retinol (Kastner
et al., 1995), as well as those lacking Raldh2
(Niederreither et al., 2000
),
display neurodevelopmental phenotypes unlike those of megalin-deficient
embryos (Willnow et al.,
1996
). Mice lacking dietary retinol or Raldh2 expression have
severe hindbrain defects (Niederreither et
al., 2000
), whereas megalin-deficient mice display abnormalities
in forebrain development (Willnow et al.,
1996
). The fact that megalin-deficient mice show no apparent
hindbrain abnormalities indicates that VE transport of maternal retinol by
megalin is not required to supply the embryo with retinol required for normal
hindbrain patterning.
Early in development, embryonic requirements for retinol may be satisfied
through simple diffusion-based transport; however, as embryonic epithelial
integrity increases and/or epithelia become stratified, trans- and
intra-epithelial transport mechanisms may be required. Since certain centers
of RA expression are located adjacent to megalin-expressing epithelia, megalin
might play a role in transport of retinol through or within stratified
epithelial layers. In this way, it might mediate delivery of retinol to cells
that express Raldh enzymes but are inaccessible to retinol. For example, sites
of synthesis of RA by Raldh3 have been described in cells located deep in the
basal layers of the ventral forebrain
(Smith et al., 2001).
Interestingly, suppression of Raldh3 expression in Pax6-deficient mice leads
to microphthalmia and forebrain defects, including absence of olfactory bulbs
(Suzuki et al., 2000
), defects
similar to those described for megalin-deficient mice
(Willnow et al., 1996
). It is
thus possible that megalin expressed by cells of the apical layers of the
forebrain and retinal epithelium (McCarthy
et al., 2002
) mediates transport of retinol to a subset of
RA-synthesizing cells located in the basal regions of the developing forebrain
and the retina. Similarly, megalin expressed on apical surfaces of the neural
tube might facilitate the transport of retinol to subapical regions where
retinoid-dependent neurons develop
(Pierani et al., 1999
).
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Megalin and the regulation of hedgehog-dependent development |
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During early development, Shh is prominently expressed in the notochord,
the floorplate of the neural tube and the zone of polarizing activity in the
limb (Marti et al., 1995).
Numerous studies have demonstrated that Shh activity is critical for the
induction, proliferation and survival of various embryonic cell types,
including ventral neural cells in the developing brain, cranial neural crest
cells and ventral neural retinal cells
(Ingham and McMahon, 2001
).
For example, mice lacking Shh have anomalies of midline structures such as the
notochord and floorplate of the early brain
(Chiang et al., 1996
) and later
display an absence of ventral neuronal cells and cranial motor neurons
(Litingtung and Chiang, 2000
)
(Table 1). The most common
structural anomaly of the developing forebrain in Shh knockout mice is HPE.
Mice lacking other components of the Shh signal transduction pathway also
display neurodevelopmental abnormalities. For instance, mice lacking Ptc
display embryonic lethality, but partial rescue of Ptc-null embryos results in
severe exencephaly (Milenkovic et al.,
1999
) and a high incidence of cerebellar medulloblastomas
characteristic of basal cell nevus syndrome
(Goodrich et al., 1997
).
Smo-null zebrafish embryos show increased apoptosis of neural tube cells and
other neural tube defects that include absence of secondary motor neurons,
synopthalmia and ventral forebrain defects
(Chen et al., 2001
;
Varga et al., 2001
)
(Table 1). Recent findings
demonstrate that mice lacking dispatched (Disp), a protein critical to the
secretion and long-range signaling of N-Shh, also display embryonic defects
similar to those of Shh/ and
Smo/ embryos (Ma
et al., 2002
). These include incomplete separation of the optic
vesicles and a lack of a floorplate, resembling early anomalies in forebrain
morphology that lead to HPE.
Since the spectrum of neurodevelopmental defects that make up the Shh-,
Smo- and Disp-deficient phenotypes includes many key features of the
megalin-deficient phenotype (Table
1), Herz and Bock have speculated that megalin is a component of
the Shh signaling pathway (Herz and Bock,
2002). This speculation was fueled by studies showing that other
members of the megalin family function as receptors for factors that influence
neurodevelopment. For example, LRP6 functions as a co-receptor with frizzled
to mediate signal transduction by the secreted signaling factor Wnt/Wg
(Pinson et al., 2000
;
Tamai et al., 2000
;
Wehrli et al., 2000
).
Similarly, very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E
receptor 2 (ApoER2) function as receptors for reelin, a protein that
influences the positioning of dentate granule cells during brain development
(Trommsdorff et al., 1999
).
Both megalin and LRP bind to midkine, a neurotrophic factor important for
survival of embryonic neurons (Muramatsu
et al., 2000
). LRP has also been shown to mediate the endocytosis
as well as the nuclear targeting of midkine, which is a requirement for its
ability to promote cell survival (Shibata
et al., 2002
). Recently, McCarthy et al. have found that megalin
binds to the N-terminal fragment of Shh (N-Shh)
(McCarthy et al., 2002
).
Furthermore, they have demonstrated that megalin functions as an endocytic
receptor for N-Shh in cultured cells
(McCarthy et al., 2002
). These
findings strengthen the idea that megalin influences Shh signaling in
developing neural tissues, perhaps explaining the basis for many of the
neurodevelopmental abnormalities observed in megalin-deficient embryos.
Thus far, a direct relationship between megalin-mediated endocytosis of Shh
and regulation of Shh signaling has not been demonstrated. There are, however,
several possible consequences of the interaction between megalin and Shh. The
binding of N-Shh might elicit direct signaling by megalin, similar to the
response of reelin binding to VLDLR and ApoER2, which activates
phosphoinositide 3-kinase (PI 3-kinase) signaling
(Beffert et al., 2002). Recent
yeast two-hybrid screening studies demonstrate the potential of numerous
cytoplasmic adaptor proteins to associate with the cytoplasmic tail of megalin
(Gotthardt et al., 2000
;
Patrie et al., 2001
;
Petersen et al., 2003
). This
raises the possibility that megalin influences a variety of cell-signaling
pathways. Interestingly, many of the adaptor proteins (e.g. Dab-1, JIP-1,
MAGI-1 and PSD-95) have roles in neurogenesis and/or neuronal functions
related to synaptic processes such as neurotransmitter receptor clustering and
signaling complex assembly. Furthermore, several of the megalin-binding
cytosolic proteins (e.g. JIP-1, Dab-2 and SEMCAP-1) regulate signal
transduction pathways (Gotthardt et al.,
2000
). Recently, a novel cytosolic adaptor protein, MegBP, has
been shown to bind to the PxxP motifs in the megalin cytoplasmic tail
(Petersen et al., 2003
). Since
MegBP interacts with several transcriptional regulators (e.g. the
SKI-interacting protein SKIP and TGF-ß-stimulated clone 22 homologous
gene (THG-1), it has been proposed that the megalin interaction with MegBP
regulates the sequestration and release of MegBP-bound transcription factors
(Petersen et al., 2003
).
Although megalin might function as a Shh signaling receptor in its own
right, the bulk of information on megalin function favors the hypothesis that
it indirectly regulates Shh signaling through endocytosis of N-Shh. As stated
above, megalin targets ligands to endosomes and transports ligands across
epithelia. Several potential consequences of N-Shh interaction with
megalin-expressing epithelial cells are depicted in
Fig. 2. The interaction might
not only mediate N-Shh uptake but also be part of an intracellular N-Shh
trafficking system. A role for megalin in Shh trafficking is supported by
evidence showing that the megalinN-Shh interaction is resistant to
dissociation at low pH and that N-Shh is not efficiently targeted to lysosomes
for degradation in megalin-expressing cells
(McCarthy et al., 2002).
Avoidance of the lysosomes may then be part of a process by which N-Shh
becomes targeted to specific cellular compartments, such as the basal or
lateral surfaces of the epithelial cells for release. This would make N-Shh
available to cells within the epithelium, thus extending the effective range
of its signaling. Such a transcytotic, epithelial transport mechanism has been
described for Wnt (Dierick and Bejsovec,
1998
), which binds to the megalin family member arrow/LRP6
(Pinson et al., 2000
;
Tamai et al., 2000
;
Wehrli et al., 2000
). This
system appears to involve formation of Wnt-containing exovesicles called
argosomes from basolateral membranes of imaginal disc epithelial cells and the
subsequent endocytosis of these vesicles by adjacent epithelial cells
(Greco et al., 2001
). The
process could establish a morphogen gradient by dispersing Wnt-containing
membrane fragments over large distances through the Drosophila
imaginal disc epithelium.
|
Another way in which megalin might influence Shh signaling is by modulating
Ptc and Smo trafficking (Fig.
2). Several recent studies indicate that there are low levels of
Ptc on the surfaces of cells and that the bulk of Ptc protein exists in
intracellular endosomal compartments (e.g. in imaginal disc epithelial cells)
(Capdevila et al., 1994;
Denef et al., 2000
). Low cell
surface levels of Ptc and increased endosomal accumulation may be the result
of megalin-mediated endocytosis. This scenario would be analogous to the roles
of LRP and VLDLR in mediating uptake of the urokinase receptor (uPAR) bound to
urokinase-plasminogen activator inhibitor-1 complexes, as well as the uptake
of the cell surface receptor tissue factor (TF) in complex with TF-pathway
inhibitor and factor VIIa (Strickland et
al., 2002
). In each of these cases, the megalin family member
regulates cell surface levels of the membrane receptors (uPAR and TF). Whether
megalin can interact with Ptc is not known; however, it is possible that N-Shh
serves as a ligand bridge similar to that in uptake of uPAR and TF by LRP and
VLDLR. In support of this possibility are the findings of Incardona et al.
showing that, after Shh binding, Ptc-Smo complexes are internalized in kidney
epithelial cells (Incardona et al.,
2002
). Further, in wing disc epithelial cells that have responded
to Shh, Ptc becomes concentrated in apical vesicles, whereas Smo becomes
distributed basolaterally (Denef et al.,
2000
). These findings indicate that, following binding of N-Shh to
epithelial cells, complex trafficking of Ptc and Smo occurs. Whether megalin
orchestrates such trafficking in epithelial cells remains to be
established.
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Conclusion and Perspectives |
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