Department of Neurobiology, Pharmacology and Physiology, University of Chicago, 947 E. 58th Street, Chicago, IL 60637, USA
Author for correspondence (e-mail:
angeliki.louvi{at}yale.edu)
Accepted 24 March 2004
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SUMMARY |
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Key words: Presenilin 1, Neuronal migration, Morphogenesis, Cortical development, Midbrain, Dopaminergic neurons, Cerebellum, Precerebellar nuclei, Facial branchiomotor neurons, -Secretase, Mouse
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Introduction |
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In the present study, we asked if the emerging complexity of the
biochemical function of presenilin is reflected in the phenotype of
Psen1 mutants (Wong et al.,
1997), focusing on CNS morphogenesis and neuronal migration.
One of the best-studied examples of radial migration is the formation of
the cerebral cortex (Marín and
Rubenstein, 2003; Rakic,
2003
). Molecular and cellular studies coupled with analyses of
natural and targeted mutations in the mouse have indicated that radial
migration is under the control of at least two signaling pathways, the one
involving reelin and its receptors (Tissir
and Goffinet, 2003
), the other dependent upon Cdk5 and its
regulatory subunits p35 and p39 (Dhavan
and Tsai, 2001
; Ohshima and
Mikoshiba, 2002
). Tangential migration, however, is a broad term
used to group together various forms of neuronal movement along the
anteroposterior or dorsoventral axis of the neural tube. Paradigms of
tangential migration include interneurons migrating from the ganglionic
eminences into the cortex and the olfactory bulb; neuronal precursors of the
cerebellum and the precerebellar system migrating from the rhombic lip; and
facial motoneurons migrating within the brainstem. Tangential migration has
been associated with a host of molecular signals, including motogenic factors,
extracellular matrix and cell-adhesion molecules, and many of the same
chemoattractive and chemorepulsive signals implicated in axon guidance
(Marín and Rubenstein,
2001
; Marín and
Rubenstein, 2003
).
We examined the development of the cerebral cortex as an example of both radial and tangential migration, and hippocampal dentate gyrus precursors, the external granular layer of the cerebellum, the precerebellar system and facial branchiomotor neurons as varied examples of tangential migration. In addition to widespread neuronal migration defects in the cortex, hippocampus, midbrain, cerebellar system and hindbrain, we documented defects in morphogenesis of the mid-hindbrain region. We found that both general modes of migration are disturbed in the Psen1 mutants, suggesting that the many disparate molecular mechanisms directly or indirectly governing neuronal migration are simultaneously affected.
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Materials and methods |
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Retrograde labeling and photoconversion
Embryos were fixed overnight in phosphate-buffered 4% paraformaldehyde. A
solution of DiI (Molecular Probes) (0.5% in ethanol, further diluted 1:10 in
0.3 M sucrose) was injected into the VIIth cranial nerve root exposed from the
ventral aspect after dissection; DiO (Molecular Probes) was injected into the
medial mass in the mutants. To label pia-attached radial glia, DiI crystals
were placed along the pia. Photoconversion of DiI into a stable product was
performed as described (Louvi and Wassef,
2000).
BrdU labeling
For labeling of dividing cells at E17.5, pregnant females were injected
intraperitoneally with a solution of BrdU (15 mg/ml in saline) at 20 µg/g
of body weight and sacrificed 4 hours later. BrdU incorporation was detected
with anti-BrdU-FITC antibody (Beckton-Dickinson) as described
(Tole et al., 1997).
In situ hybridization and immunohistochemistry
Both were performed as described (Louvi
and Wassef, 2000). RNA probes used were for the following genes:
ß-tubulin (type III), Cdh6, Cdh8, Dab1, Dlx2, ephrin A5,
F-spondin, Gad67, Gata3, Gbx2, Hes5, Hoxb1, Islet1, Lmx1a, Lmx1b, Math1,
NeuroD, Pax6, Phox2b, p75, Prox1, reelin, Rora, Scip, Tag1, Tbr1
and Th. RC2 mAb (1:2) was from Developmental Studies Hybridoma
Bank.
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Results |
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Despite the defect documented at the onset of FBM neuron migration, a small
fragmented facial (VII) nucleus was eventually formed, as demonstrated by in
situ hybridization with Islet1
(Ericson et al., 1992) at
E16.5 (Fig. 1I,J), indicating
that at least a subset of FBM neurons complete their migratory routine.
Therefore, in the absence of Psen1, FBM neurons differentiate, but fail to
migrate properly. This defect thus reflects an involvement of Psen1 in
tangential neuronal migration.
Further potential migration defects were noted, but studied in less detail.
Two other hindbrain somatic motor nuclei were abnormal: the nucleus abducens
(VI), differentiating within r5/6, was fragmented; while the hypoglossal (XII)
nucleus appeared fused in an aberrant dorsomedial position in r8. Extreme
disorganization of hindbrain motoneurons was already obvious at E11.5,
evidenced by Isl1 expression (data not shown). Finally, Pax6
expression in neuronal progenitors was downregulated in the hindbrain of
Psen1 mutants at E11.5 (Fig.
1K,L). Unexpectedly, Pax6-positive cells formed discrete
streams in ventral r3 and r5/6 (arrows in
Fig. 1L). Taken together, these
data suggested that the null mutation in Psen1 affected the migration
of somatic motoneurons in the hindbrain. These observations correlate well
with the strong expression of Psen1 in most hindbrain nuclei and the
facial nucleus in particular (Tanimukai et
al., 1999) (A.L., unpublished).
Defects in glia-guided radial migration of cortical neurons
In light of our observations and reports that have indicated cortical
dysplasia with focal heterotopias in three independently generated
Psen1 strains (Hartmann et al.,
1999; Handler et al.,
2000
; Yuasa et al.,
2002
), we analyzed cortical development, as an example of radial
migration. Psen1 mutants are smaller than wild type, with abnormal
overall brain morphology, in part because of severe CNS hemorrhage (Wong et
al., 1996; Shen et al., 1996). Because they die perinatally, our analyses were
limited to late embryonic stages. Cortical stratification was perturbed in the
Psen1 mutants at E16.5, as evidenced in Nissl preparations
(Fig. 2A-D). Psen1
itself is expressed in wild-type cortex in the ventricular zone (VZ), the
intermediate zone (IZ) where cells migrate, the subplate (SP) and the cortical
plate (CP) at E17.5 (Fig.
2E,F). Neuronal differentiation, assessed by class III
ß-tubulin gene expression, appeared to have proceeded at comparable
levels in wild-type and Psen1 mutant littermates at late stages (data
not shown). Indeed, neuronal differentiation occurs prematurely (and in a
region-specific manner) at early stages in Psen1 mutants, but reverts
to wild-type rates after E12.5 (Handler et
al., 2000
).
|
To assess migration to and within the cortical plate at E17.5, we used a
panel of layer-specific markers for genes [reelin, Scip (Pou3f1
Mouse Genome Informatics), Tbr1 and p75
(Ngfr Mouse Genome Informatics)]. The earliest generated
marginal zone (MZ), which is identified by reelin expression, formed normally
in the Psen1 mutants, indicating that migration of Cajal-Retzius
cells was unaffected. The layer of Cajal-Retzius cells appeared nevertheless
disrupted, perhaps owing to overall reduction of cell density in the MZ
(Hartmann et al., 1999).
Expression of Scip is confined to a subpopulation of prospective
layer V neurons, but is also high in the subventricular (SVZ) and intermediate
(IZ) zones at late embryonic stages
(Frantz et al., 1994
). In
Psen1 mutants, Scip expression was indeed detected within
the CP; strikingly, however, many neurons expressed Scip ectopically
along a radial path, as though unable to execute their migratory program
properly (Fig. 2I-L). At late
embryonic stages, Tbr1 is expressed in the subplate and future layer
VI, as well as in superficial layers I-III
(Bulfone et al., 1995
).
Expression of Tbr1 in the Psen1 mutants again revealed
apparent abnormal migratory behavior of differentiating cortical neurons
(Fig. 3A,B). Expression of
p75, which was confined to the subplate and layer VI at this stage
(Mackarehtschian et al.,
1999
), was not only downregulated in the Psen1 mutants,
but also appeared patchy, lacking normal gradients, and severely disorganized
(Fig. 3C,D). Furthermore,
expression of cadherin 6 and cadherin 8, which were detected, respectively, in
future layers II-IV and V/VI (Inoue et
al., 1998
), was downregulated overall in the CP and nearly absent
in the IZ of Psen1 mutants (Fig.
3E,F; data not shown).
|
The molecular data described above, in conjunction with the abnormal distribution of BrdU at E17.5, pointed, albeit indirectly, to a defect in radial glia. To directly examine its morphology, we labeled pia-attached radial glia by placing small DiI crystals along the pial surface of the brain at E16.5. In wild type, radial glia processes were rather straight and regular, resembling well-combed hair, and extended to the ventricular surface. By contrast, in the Psen1 mutant, radial glial processes appeared tangled (Fig. 4A-D). Morphological changes in radial glia were confirmed by RC2 immunohistochemistry (Fig. 4E,F). To assess the association of neurons with radial glia, DiI was photoconverted and sections were processed to show Scip expression. In wild-type cortex, Scip-expressing neurons were smoothly juxtaposed to radial glial processes (Fig. 4G). In the mutant, thick masses of Scip-expressing cells and their processes overlaid clumps of radial glia, suggesting stalled or defective migration (Fig. 4H). Both molecular and morphological observations therefore pointed to defects in cortical proliferation and radial migration, at least in part due to abnormalities in radial glial cells.
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Migration defects in the midbrain
We next analyzed the effects of Psen1 loss of function in the midbrain,
where neuronal migration has not been studied extensively. We noticed that
expression of F-spondin (Spon1 Mouse Genome Informatics), which is
implicated in spinal cord commissural axon pathfinding
(Burstyn-Cohen et al., 1999)
was severely diminished in the Psen1 mutants at E10.5 and E11.5
(Fig. 6A,B; data not shown).
However, ventral midbrain expression of other markers (Shh, Lmx1a, Lmx1b,
Pax6) between E10.5 and E12.5 appeared normal
(Fig. 6C,D; data not shown).
Moreover, the anlagen of the oculomotor complex (III) and the trochlear (IV)
motor nucleus, identified, respectively, by
Isl1/Gata3/Phox2b expression, or Phox2b
expression alone (Pattyn et al.,
1997
; Nardelli et al.,
1999
; Agarwala and Ragsdale,
2002
) formed in the Psen1 mutants
(Fig. 6E,F; data not shown);
the former, however, was smaller and had fewer
Isl1/Gata3-positive cells migrating anteriorly
(Fig. 6F).
|
Finally, the two bilateral streams of cells emigrating caudally from the
mesencephalic tract of the trigeminal nerve (tmesV) into dorsal r1, identified
by Isl1 expression at E11.5
(Fedtsova and Turner, 2001),
were considerably underdeveloped (data not shown).
Defects in tangential migration in the brainstem
Next, we focused on the development of the cerebellum and precerebellar
system for several reasons: the rhombic lip is a site of tangential (posterior
to anterior and circumferential) migrations par excellence; Psen1 is expressed
in the cerebellum, the pontine nucleus and the inferior olive
(Lee et al., 1996;
Tanimukai et al., 1999
); and,
finally, the caudal midbrain appears to have overgrown at the expense of an
abnormal cerebellum.
Prenatal cerebellar development relies on tangential migration of the
proliferative granule cell precursors (GCPs) from the anterior rhombic lip
over the developing cerebellum, and ascension of Purkinje cells (PCs) from the
neuroepithelium along radial glia fibers
(Altman and Bayer, 1997). In
Psen1 mutants, the cerebellum was smaller with its two halves
remaining separate posteriorly, indicating incomplete fusion at the midline
(Fig. 7A-H). To examine GCPs at
E17.5 we analyzed Math1 (Atoh1 Mouse Genome
Informatics) (Ben-Arie et al.,
1997
) and Pax6
(Engelkamp et al., 1999
). A
well-developed external granule layer (EGL) covered the cerebellum in wild
type; in the Psen1 mutants, however, GCPs failed to reach the
anterior-most part of the cerebellum (Fig.
7A-B,E-F,G-H), where a GCP-free medial region developed (arrow in
Fig. 7B,D). In addition, PCs,
which are identified by Rora expression
(Hamilton et al., 1996
), had
clustered beneath the displaced EGL (Fig.
7C,D,I,J; compare 7A with 7C, 7B with 7D, 7G with 7I, and 7H with
7J).
|
Development of the precerebellar system, however, relies on tangential
migrations from the posterior rhombic lip
(Altman and Bayer, 1997;
Rodriguez and Dymecki, 2000
).
For example, pontine nuclei are formed by long-range migration of postmitotic
precursors along a superficial circumferential trajectory. We used
Pax6 as a marker of the pontine migratory stream and nuclei proper
(Engelkamp et al., 1999
;
Yee et al., 1999
). Pontine
nuclei were underdeveloped in the Psen1 mutants, as evidenced by
morphology and Pax6 expression and the migratory stream was
underpopulated with migratory precursors, only a few of which appeared to
reach their final destination in the pons
(Fig. 7K,L). Instead, a cluster
of Pax6-positive cells accumulated ectopically
(Fig. 7L, arrow). Finally, the
inferior olive appeared poorly assembled (data not shown). Thus, the pontine
nuclei appear to represent another example of a tangential migration defect in
the absence of Psen1.
Defects in morphogenesis of the mid/hindbrain
Gross morphological and gene expression analyses indicated defects in the
derivatives of the mid/hindbrain (see Fig.
7A-D). A single-dose BrdU pulse at E17.5 identified the
compromised EGL in the Psen1 mutants
(Fig. 8A,B), and numerous
proliferating cells in the GCP-free ectopic region rostral to the vestigial
cerebellum, as well as in the caudal midbrain
(Fig. 8B). Reelin expression
confirmed that the EGL was abnormal, and emphasized the dramatic overgrowth of
the inferior colliculus (the caudal part of dorsal midbrain), normally thinner
than the superior colliculus (the rostral part) at this stage
(Fig. 8C,D; asterisk in D). The
expression domain of ephrin A5 (Donoghue
et al., 1996) was dramatically enlarged, indicating that the
inferior colliculus was indeed expanded in the Psen1 mutants
(Fig. 8E,F).
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Discussion |
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Psen1 and Cdk5 mutants: similarities and implications
The array of neuronal migration defects in the Psen1 mutants is
strikingly reminiscent of those observed in embryos with targeted mutations in
the Cdk5/p35/p39 pathway (reviewed by
Dhavan and Tsai, 2001;
Ohshima and Mikoshiba, 2002
).
In the cerebral cortex, Cdk5 mutants exhibit defects confined to the
late-migrating, glia-guided cortical neurons. Cdk5 and Psen1
mutants share a surprisingly similar defect in the positioning of FBM,
complete with the appearance of an ectopic mass of postmitotic neurons in the
ventral hindbrain. Dhavan and Tsai (Dhavan
and Tsai, 2001
) have previously suggested that Cdk5 and its
regulatory subunits p35 and p39 are crucial regulators of neuronal migration.
Indeed, p35 mutants display an atypical mode of migration in the
cortex, associated with disrupted neuronal-glial interactions
(Gupta et al., 2003
). The
similarities in the mutant phenotypes we document indicate the possible
convergence of different pathways towards similar intracellular factors and
could be the manifestation of molecular interactions between the Psen1 and
Cdk5 pathways. Psen1 has been reported to interact with Cdk5 in
many ways. On the one hand, Cdk5/p35 has been reported to bind and
phosphorylate ß-catenin and to regulate ß-catenin/Psen1 interactions
(Kesavapany et al., 2001
).
Cdk5/p35 is, on the other hand, involved in the regulation of
N-cadherin-mediated adhesion in cortical neurons, and N-cadherin itself is a
-secretase substrate (Kwon et al.,
2000
; Marambaud et al.,
2002
). Dab1, which is downregulated in Psen1 mutants, is
also a substrate for Cdk5/p35, and interacts with APP in yeast two-hybrid
screens (Howell et al., 1999
;
Keshvara et al., 2002
).
Finally, deregulation of Cdk5 activity through accumulation of p25 (a cleavage
product of p35) has been implicated in Alzheimers disease itself
(Tseng et al., 2002
).
In comparing Psen1-related neuronal migration phenotypes to the phenotypic
consequences of other mutations, it is noteworthy that recent observations
suggest an intersection of pathways controlling molecular mechanisms of
neuronal migration and axonal transport. In legs at odd angles
(Loa/Loa) embryos, which carry a missense mutation in dynein
cytoplasmic heavy chain, migrating FBM neurons bifurcate and a double nucleus
eventually forms (Hafezparast et al.,
2003), not unlike the fragmented facial nucleus of the
Psen1 mutants. Cytoplasmic dynein is a major motor complex involved
in retrograde transport with reported roles in neuronal migration, neurite
outgrowth and axonal transport of microtubules, neurofilaments and organelles
(reviewed by Morris, 2000
;
Terada and Hirokawa, 2000
).
Interestingly, the dynein pathway component Nudel is a substrate for Cdk5
(Niethammer et al., 2000
;
Sasaki et al., 2000
),
suggesting a further link. Moreover, embryos lacking another motor protein,
kinesin KIF1Bß, also display defective development of the facial nucleus
(Zhao et al., 2001
). Notably,
Psen1 has recently been implicated in anterograde (kinesin-based) axonal
transport (Pigino et al.,
2003
).
Psen1 and Small eye mutants: the role of Pax6
It is quite clear that the abnormalities we observe in the Psen1
mutants cannot be explained only by the Psen1/Cdk5 relationship. Our analysis
revealed a second process that appears to be affected by Psen1 malfunction,
namely Pax6 regulation. We showed that, in the Psen1 mutants in
general, Pax6 expression is downregulated (in the VZ of the
developing cortex, the hindbrain and the precerebellar nuclei) or delayed (in
the rhombic lip), and is relatively unaffected only in the ventral midbrain at
early stages. The Pax6 expression changes we observe offer a
plausible explanation for part of the phenotypes we documented. Hints of a
possible relationship between Pax6 and Psen1 come from the wealth of
information available on the small eye (Sey) mouse, which lacks
functional Pax6 protein (Hill et al.,
1991). In the Sey/Sey developing cortex neuronal
migration defects occur primarily at late stages, indicating that they might
be radial glia-dependent (Schmahl et al.,
1993
; Caric et al.,
1997
). Indeed, radial glia are lost in the Sey/Sey cortex
(Götz et al., 1998
).
Moreover, in the Sey/Sey mouse, loss of Pax6 leads to excessive
migration of interneurons from basal brain into the cortex
(Chapouton et al., 1999
;
Yun et al., 2001
), hindbrain
motor neurons are incorrectly specified
(Ericson et al., 1997
;
Osumi et al., 1997
) and
rhombic lip-derived structures severely affected
(Engelkamp et al., 1999
).
Widespread downregulation of Pax6 expression as such documented in
the Psen1 mutants is therefore expected to affect much the same
processes. Thus, the defects in radial-glia dependent cortical migration,
radial glia differentiation in the VZ, incorrect migration of interneurons
into the cortex and of pontine precursors in the precerebellar system could be
consequences of insufficient levels of Pax6 expression. Although no direct
relationship between Pax6 and Psen1 has been described, studies in
Drosophila have linked Notch signaling with the regulation of the
Pax6 ortholog eyless (ey) during eye development,
suggesting that ey may act, in some fashion, downstream of Notch
signal input (Kurata et al.,
2000
; Kumar and Moses,
2001
; Kenyon et al.,
2003
). One possibility, therefore, is that Psen1 influences Pax6
function via the Notch pathway.
Morphogenesis of the cerebellar system, tangential migrations and guidance molecules
We found that loss of Psen1 function leads to abnormalities in glia-guided
radial migration, as well as tangential migration, and to defects in
cerebellar morphogenesis. We determined that the latter is accompanied by the
downregulation of Gbx2 in the anterior hindbrain. Otx2 and Gbx2 act
antagonistically to position the isthmic organizer (reviewed by
Wurst and Bally-Cuif, 2001),
and although Otx2 appears unaffected in the Psen1 mutants,
Gbx2 downregulation implies that the isthmic organizer might be
deregulated. Interestingly, in the absence of functional Gbx2, the inferior
colliculus is dramatically thickened
(Wassarman et al., 1997
), a
phenotype also observed in the Psen1 mutants. In addition to
Gbx2 downregulation, incorrect regulation of Math1 may
partly account for the cerebellar morphogenetic phenotype: downregulation of
Math1 in the medial rhombic lip is essential for cerebellar midline
fusion (Louvi et al., 2003
).
What could account for the failure of CGPs to reach the anterior-most part of
the cerebellum? Although we have not examined this issue in detail, we note
that the guidance molecule Erbb4, subject to
-secretase processing
(Ni et al., 2001
), is
expressed in GCPs and in the caudal rhombic lip
(Dixon and Lumsden, 1999
),
explaining perhaps part of the migration defects we observe. In addition, it
is known that precerebellar nuclei precursors interpret netrin as a
chemoattractant (reviewed by Wingate,
2001
) and this property could account for the defects in the
pontine migratory stream and nuclei. Interestingly, of all netrin receptors,
the migratory pontine cells express on their leading processes solely DCC
(Yee et al., 1999
) and not
surprisingly, pontine nuclei are absent in netrin 1 and Dcc mutant
mice (Serafini et al., 1996
;
Fazeli et al., 1997
).
Moreover, cells migrating to the inferior olive express Dcc (in
addition to other netrin receptors) and netrin signaling plays a role in the
finer subdivision of this nucleus. Although netrin expression appears
unaffected in the ventral hindbrain of Psen1 mutants, Dcc was
recently shown to undergo Psen1-dependent
-secretase processing
(Taniguchi et al., 2003
),
suggesting that the interpretation and/or reception of netrin signaling is
defective in the absence of functional Psen1.
Presenilins and the cytoskeleton: a mechanistic explanation?
As radial and tangential modes of migration are affected in the
Psen1 mutants, it seems plausible that fundamental cellular
mechanisms required for cell movement might be perturbed in the absence of
functional Psen1 protein. In preparation to move, cells extend a leading
process sensing the immediate environment, followed by translocation of the
nucleus into the leading process and subsequent retraction of the trailing
process. The first step heavily depends on polymerization and reorganization
of actin microfilaments and is controlled by Rho family GTPases
(Ridley, 2001), while the
second step relies on microtubules (Morris
et al., 1998
; Lambert de
Rouvroit and Goffinet, 2001
;
Nadarajah and Parnavelas,
2002
). Evidence suggests that Psen1 may indeed interact with
cytoskeletal elements. First, in hippocampal cultures, Psen1 associates with
microtubules and microfilaments in a developmentally regulated manner and is
localized in lamellipodia and filopodia of neuronal growth cones
(Pigino et al., 2001
). Second,
the microtubule-associated protein Tau can associate with Psen1 in cultured
cells and to a lesser extent in brain extracts
(Takashima et al., 1998
).
Third, presenilins can interact in vivo and in vitro with at least two
actin-binding family members, filamin A and filamin homolog 1
(Zhang et al., 1998
). In
Drosophila, filamin interacts genetically and physically with
presenilin (Guo et al., 2000
).
More importantly, in humans, mutations in filamin A prevent migration of
cerebral cortical neurons causing periventricular heterotopia
(Fox et al., 1998
). Finally,
in Drosophila, Psn (presenilin) mutations disrupt the
spectrin cytoskeleton (López-Schier
and St Johnston, 2002
), whereas Psen1-dependent
-secretase
cleavage of E-cadherin leads to its dissociation from the cytoskeleton
(Marambaud et al., 2002
).
Interestingly enough,
-spectrin accumulates in cytoplasmic inclusions
in the brains of individuals with Alzheimers disease
(Sangerman et al., 2001
).
Thus, evidence, albeit circumstantial, exists to suggest a link between
presenilins and the cytoskeleton that could provide a mechanistic explanation
for some of the migration defects seen in the Psen1 mutants.
In conclusion, our analysis established a novel role for Psen1 in neuronal
migration and morphogenesis while revealing the complex relationship between
Psen1 and specific cellular events and biochemical pathways that affect
migration. The extent to which this complex phenotype directly or indirectly
reflects the diversity of substrates that can be affected by -secretase
remains to be determined. Nevertheless, our data implicate Psen1 with a roster
of specific cellular pathways and demonstrate that the Psen1 loss-of-function
phenotypes reflect the many developmental processes simultaneously affected by
this mutation.
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ACKNOWLEDGMENTS |
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Footnotes |
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