1 EPHE Quantitative Cell Biology, INSERM EMI 343, IFR 122, University
Montpellier 2, 34090 Montpellier, France
2 Laboratoire de Neurobiologie Cellulaire et Moléculaire, UPR 9040 CNRS,
1 Avenue de la Terrasse, 91198 Gif sur Yvette, France
3 INSERM UMR 623, IBDM Campus de Luminy, Case 907, 13288 Marseille Cedex 09,
France
4 INSERM U.583 Institut des Neurosciences de Montpellier (INM), Hôpital St
ELOI, 80 rue Augustin Fliche, 34295 Montpellier Cedex 5, France
* Author for correspondence (e-mail: mrossel{at}univ-montp2.fr)
Accepted 5 January 2005
![]() |
SUMMARY |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: Reeler mutant, Dab1, Hindbrain, Neuronal migration
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The exact mechanisms involved in the reeler-like migration defects
have not yet been elucidated. The aberrant layer formation documented in
reeler and scrambler mutants may be related to defects in
radial glia guided migration (Marin and
Rubenstein, 2003). It has been shown that cortical neurons follow
the long process of radial glial cells that extend from the lumen to the pial
surface, performing a radial migration. Various lines of evidence indicate
that the reeler phenotype could, at least partly, be due to impaired
detachment of neuronal precursors from radial glial processes, to
disorganization of radial glial scaffold, or to abnormal glial endfeet
attachment at the pial surface (Tissir and
Goffinet, 2003
).
Defects in neuronal positioning in several other CNS regions have been
observed in reeler mice. Study of migrating adult olfactory
interneuron precursors have shown that reelin is necessary for the switch from
tangential chain migration to radial individual migration in the olfactory
bulb (Hack et al., 2002). In
the spinal cord, a particular neuronal population that originates from the
same precursor cells as motoneurons, the sympathetic preganglionic neurons, is
ectopically positioned in the absence of reelin
(Phelps et al., 2002
).
The vertebrate hindbrain contains specialized nuclei with different
functions and positions, which is the result of complex migrations that take
place over a period of several days during embryonic development
(Chandrasekhar, 2004). Most
studies performed on hindbrain motoneuron nuclei in reeler hindbrain
have been carried out after birth or in adult animals, except for the study of
the facial nucleus phenotype described by Goffinet
(Goffinet, 1984
). Separate
studies reported defects for the trigeminal, the cochlear nucleus, the nucleus
ambiguous and the facial nuclei (Fujimoto
et al., 1998
; Goffinet,
1984
; Martin,
1981
; Terashima et al.,
1993
; Terashima et al.,
1994
). The common phenotype was a variable disorganization of the
considered nucleus, the reason for this disorganization remaining unknown.
We used molecular markers that identify specific hindbrain neuronal populations in order to follow the migration and differentiation of these nuclei in the early development of the reeler mouse, as well as nuclei position in mutants for Dab1 and reelin receptors. We demonstrate that ectopic positioning of hindbrain nuclei in mutant embryos is a more general deficiency of those nuclei that undergo radial migration, and includes facial visceral motoneurons and olivocochlear efferents. In all cases, the affected nuclei remain at the position where they normally switch from dorsolateral to radial migration. We conclude that the phenotype results from the impairment of the final step of migration where the neurons migrate ventrally along (or parallel to) radial glial fibers.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In situ hybridization and immunohistochemistry
Embryos were fixed in 4% paraformaldehyde (PFA) overnight at 4°C. In
situ hybridization (ISH) on whole-mount preparation and cryostat sections were
carried out as described by Carroll et al.
(Carroll et al., 2001). ISH on
vibratome sections has been described previously
(Poluch et al., 2003
). The
following cDNA probes were used: islet 1
(Pfaff et al., 1996
), c-Ret
(Pachnis et al., 1993
), Phox2b
(Pattyn et al., 1997
), Gata3
(Karis et al., 2001
), Tbx20
(Kraus et al., 2001
), Lhx4,
ER81 (Gavalas et al., 2003
),
ApoER2 and VLDLR (Trommsdorff et al.,
1999
). Double in situ hybridization/immunohistochemistry were
performed as described previously (Carroll
et al., 2001
), on floating vibratome sections. Indirect
immunohistochemistry analyses were performed on vibratome sections using
secondary peroxidase-conjugated antibody.
The following antibodies were used for double immunofluorescence experiments on vibratome sections: mouse antiislet 1 (39.4D5) and RC2 (Developmental Studies Hybridoma Bank). Secondary antibodies, FITC-conjugated anti-mouse IgG FC-fragment specific (Sigma F5897) and Cy3-conjugated anti-mouse IgM (Jackson Laboratories) were applied for islet 1 and RC2 labeling, respectively. Images were acquired with a Leica confocal microscope and Imaris-image processing software was used for further image analysis.
Retrograde labeling of cranial nerves
E11.5 and E12.5 embryos were dissected and fixed in 4% PFA. DiI injections
were performed as previously described
(Goddard et al., 1996). DiI
was applied to the VII nerve or to the VIIIth ganglion of both sides of the
embryos, and allowed to diffuse for 2 to 5 days. Alternatively, we injected
DiI in one otocyst of the embryo to observe contralateral subpopulations.
Hindbrains were then dissected and mounted in glycerol. In older embryos
(E12.5), the brains were then embedded in 2% agarose and vibratome sectioned
(60-80 µm). Image analysis was performed with either a standard Nikon
epifluorescence microscope or a Biorad confocal microscope for optical
sections.
Photoconversion of DiI was performed on vibratome sections as described
previously (Singleton and Casagrande,
1996), then refixed in 4% PFA, dehydrated through ethanol series
and stored at -20°C until ISH processing.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
We will describe first the migration of the different MNP throughout hindbrain development in wild type, and how the MNP are affected in reeler mutants (see Fig. 10 for a diagrammatic representation).
|
Facial (VII) motoneurons are born in r4 and form a stream of cells
migrating caudally through r5 and into r6, before migrating ventrally toward
the pial surface in r6 (Fig.
1A) (Garel et al.,
2000). This process is complete by E15.5
(Fig. 1G). At this later stage,
the VII nucleus comprises two lobes, a medial and lateral one
(Fig. 1G, arrowheads). In
reeler embryos, from E12.5 to E14.5, the VII nucleus is present in
its normal position (Fig.
1B,D,F) whereas at E15.5, the medial lobe is reduced relative to
the wild type (Fig. 1H,
arrowhead). Using Lhx4 and ER81 transcription factor
expression as markers of MN identities
(Sharma et al., 1998
;
Gavalas et al., 2003
), we
observed that in reeler mice, the medial Lhx4+ cell group is
reduced (Fig. 2A,B,
arrowheads), whereas the lateral ER81+ cell group appears to be more
scattered than in the wild type (Fig.
2C,D, arrowheads). We conclude that despite a global
disorganization of the VII nucleus, the two populations of VII neurons are
correctly specified.
|
In vibratome sections performed at the r5 level of E13.5 control embryos, the FVM appears as a compact group of islet 1-expressing cells close to the pial surface (Fig. 3A,F; arrow in 3A). In reeler hindbrain at the same rostro-caudal level, the FVM is absent from its normal position (Fig. 3B, circle), but a prominent group of ectopically positioned cells is present at the ventricular side (Fig. 3B, arrowed stippled circle). In addition, a more diffuse ectopic group is observed in an intermediate position (Fig. 3B, arrowhead). In cryostat sections, the same result was observed with ectopic groups of cells within the depth of the neural tube (Fig. 3G).
|
DiI injection into the VII nerve at E11.5 and E12.5 labels axons and cell bodies of the FVM and VII facial nucleus. We will focus mainly on the FVM, as VII motoneuron migration appears similar in wild type and reeler mutants until E13.5. Our results indicate that, in reeler hindbrain (Fig. 4B,D), as in control embryos (Fig. 4A,C), the FVM neurons are born normally in r5 and migrate laterally after exiting the ventricular zone. At E12.5, transverse sections of control embryos indicated that DiI-labeled cells have migrated ventrally toward the pial surface (Fig. 4E). However, in reeler mutants, these cells remained in a lateral and intermediate position (with respect to the dorsoventral axis) (Fig. 4F, stippled area). Although cell bodies are ectopically located in reeler mutants, their axons extend normally and exit the hindbrain at the correct position, concomitantly with the axons of facial motoneurons (Fig. 4B,D). Altogether, these results demonstrate that the FVM neurons remain in an intermediate position, which probably corresponds to the intermediate group of cells labeled by islet1 and c-Ret (Fig. 3).
|
Using markers of VEN and OC nuclei, Gata3 and Tbx20, we compared the
position of the two nuclei in control and reeler mice
(Karis et al., 2001;
Tiveron et al., 2003
;
Kraus et al., 2001
). In
control hindbrain, Gata3 labeled the reticular formation in a characteristic
`butterfly shape', as well as the OC neurons, which form a dense column of
Gata3-expressing cells at the pial surface
(Fig. 5A, arrows in 5C,E). In
reeler embryos, reticular formation labeling was identical to control
embryos but the OC precursor column was barely visible at the pial surface
except for a small group of Gata3-positive cells observed at the edge of the
reticular formation (Fig. 5B,F,
unfilled arrowhead). In vibratome sections of the same embryos, at r4 and r5
levels, ectopic groups of Gata3-positive cells were observed
(Fig. 5D,F, black arrowheads).
Similar results were obtained on cryostat sections (data not shown).
|
In order to assess VEN and OC positions in reeler mutants, we performed DiI-retrograde labeling from the cochlear and VIIIth ganglion (injected both sides, Fig. 6A,B) in wild type and reeler mutants at E12.5. In Fig. 6A, transverse sections of control hindbrain showed that VEN was visible in a dorsal position near the ventricular zone, with the OC group in a ventral location. In reeler hindbrain, VEN was positioned normally; however, OC cells were found in an ectopic position, close to the VEN (Fig. 6B).
|
Our data indicate that the OC precursor cells are specifically affected in reeler mice. They share a common migratory step with the FVM neurons: a final ventral migration parallel to radial glia fibers toward the pial surface. Both populations, OC and FVM neurons, failed to perform their final radial migration in the absence of reelin signaling.
Reelin and Dab1 are expressed early in hindbrain development
Reelin and Dab1 are expressed in the early steps of hindbrain development
(Carroll et al., 2001). As we
observed specific migration defects in r4 and r5, we examined in detail reelin
and Dab1 expression patterns in the r4-r6 area
(Fig. 7). Using whole-mount
ISH, we observed an increase in reelin expression from E11.5
(Fig. 7A) to E12.5
(Fig. 7B), with a strong
expression localized in r6, close to the pial surface. We performed reelin and
Dab1 ISH on serial vibratome sections. We observed areas with strong
reelin expression at r4, r5 and r6 levels, close to the pial surface
(Fig. 7D,G,J). Dab1 was
strongly expressed in a region that includes the OC cells in r4
(Fig. 7E), the FVM in r5
(Fig. 7H) and the migrating
branchial motoneurons in r6 (Fig.
7K). In order to correlate reelin expression and motoneuron
position, combined reelin ISH followed by islet 1 immunohistochemistry was
performed. The settling position of islet-positive motoneurons showed strong
reelin expression; whereas the tangentially migrating motoneurons are found in
a reelin-negative area (Fig.
7C,F,I).
|
|
Hindbrain reeler-like phenotype displayed by scrambler mutants but not by Reln receptor mutants
Genetic and biochemical evidence has placed reelin, the ApoER2/VLDLR
receptors and Dab1 in a common signaling pathway that involves the binding of
reelin to ApoER2/VLDLR receptors and then the recruitment and phosphorylation
of the intracellular adaptor molecule Dab1
(Herz and Bock, 2002). Because
in the brain and spinal cord, mutants for reelin receptors and Dab1 display
comparable phenotypes to reeler mutants, we investigated whether the
components of this pathway were involved in the phenotype observed in the
hindbrain.
We analyzed hindbrain motoneuron migration in scrambler mutants by islet 1 ISH on E15.5 embryos. A comparable phenotype to that of reeler was observed in scrambler mutants: namely an absence of islet 1 labeling at the position of OC/FVM at the pial surface and a disorganization of the VII nucleus cells (Fig. 9C). Ectopic groups of cells were observed deeper within the neural tube in vibratome sections (data not shown).
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Despite their ectopic positioning, the affected nuclei expressed the appropriate molecular markers. Thus, the migration defect is not due to re-specification of these cell types. Our results show for the first time that the migration of several types of hindbrain neurons is separated into two major distinct steps: a dorsolateral reelin-independent migration and a ventral reelin-dependent migration.
Normal cell specification but perturbed organization of the facial nucleus
It has previously been shown that the facial nucleus, even though in the
correct rostro-caudal position, is abnormally shaped in reeler
neonates (Goffinet, 1984). We
observed reelin expression in the area of settlement of the facial nucleus,
and Dab1 expression by most of the facial motoneurons. Our results show that
in reeler and scrambler mice, the facial nucleus performs a
normal tangential migration and that the last phase of migration is affected.
This defect is apparent for the medial lobe of the nucleus at E14.5; however,
motoneuron identities are conserved as deduced from Lhx4 and ER81 expression
analysis. These results fit with the observations of Terashima et al., who
showed that the muscle targets of this nucleus were correctly innervated in
reeler mice (Terashima et al.,
1993
). Dab1 mutants display a hindbrain reeler-like
phenotype, and the compound Dab1/p35 mutants exhibit a complete failure of
facial neuronal caudal migration (Ohshima
et al., 2002
). p35 is the activator of Cdk5, which is involved in
cortical neuron migration (Ko et al.,
2001
). These results, and the study by Beffert et al. on cortical
development, suggest that Cdk5 and reelin act through parallel pathways that
might share common effectors in the regulation of facial nucleus migration
(Beffert et al., 2004
;
Ohshima et al., 2002
).
Several factors are known to play a role in regulating facial motoneuron
migration. Hoxb1 determines the primary specification of the inner ear
efferents, facial motoneurons and their caudal migration
(Goddard et al., 1996;
Studer et al., 1996
). The
influence of different additional signals is necessary for the facial complex
migration. Nkx6.1 is required for facial motoneuron migration into r5 and r6.
Premature turning and migration arrest in Nkx6.1 mutants is associated with
ectopic expression of cell surface receptors such as Ret and Unc5h3
(Muller et al., 2003
). Double
Nkx6.1/Nkx6.2 mutants show a complete lack of migration
(Pattyn et al., 2003
). How
reelin signaling interacts with the other signals and how only a subset of
facial MNP respond to reelin signaling remain to be clarified.
Reelin signaling is necessary for final ventral migration of FVM and OC neurons
Not much is known about the molecular mechanisms involved in the migration
of visceral motoneurons and cochlear efferent neurons. Previous descriptions
of FVM and OC migration during hindbrain development have reported the
presence of cochlear efferents in a ventral position at E12.5 in r4 and r5,
where they settled in a location medial to FVM.
(Auclair et al., 1996;
Bruce et al., 1997
;
Fritzsch and Nichols, 1993
).
Our results suggest that two groups of cells are intermingled at r5 level in
wild-type embryos: namely OC and FVM precursor cells
(Fig. 10).
Inner ear efferent cells, which have an r4 origin, split into two groups
(VEN and OC) with distinct migratory behaviors. A recent study of their
development and migration indicated that the correct migration of VEN neurons
into a lateral position depends on the maintenance of Mash1 expression,
whereas OC migration is Mash1 independent
(Tiveron et al., 2003). In
addition, EphB2 has been shown to be essential for VEN contralateral axonal
projections and axon guidance, and is necessary for normal vestibular function
(Cowan et al., 2000
). In
reeler mice, we observed a defect in the ventral migration of the OC
neurons, which remain in a dorsolateral position near the VEN population,
which is itself unaffected. As is the case for FVM neurons, the OC population
appears to stop at the point where they should separate from the VEN and start
their radial migration. OC neurons are characterized as lateral and medial OC
(LOC and MOC) according to their migration position near the pial surface and
their projections. VEN and MOC have contralateral projections toward the
periphery; VEN remain in a dorsal position, whereas MOC settle in a ventral
position. We were not able to demonstrate whether OC subpopulations were
affected equally because a few cells were still able to migrate ventrally in
reeler mutants. However, as we only observed these cells on the
ipsilateral side after retrograde labeling, the LOC might be less affected.
Detailed analyses at different stages of development are needed to clarify
this question.
Our data demonstrate that a general migratory step, the radial migration toward the pial surface, shared by most hindbrain branchial and visceral motoneuron-derived efferents, as well as by OC efferents, is under the control of the reelin signaling pathway, and indicate a possible common ontogenetic origin of these three cell groups.
Reelin signaling in the hindbrain: comparison with other reelin-dependent migrations
The absence of reelin seems to have opposing effects in different
situations. In the spinal cord, reelin absence allows preganglionic neurons to
migrate ectopically along radial glia toward the central canal; in the
olfactory bulb, absence of reelin causes accumulation of tangentially
migrating precursors where they should disperse into the bulb; in the
reeler cortex, neurons fail to detach from their glial guides
(Tissir and Goffinet, 2003).
In spite of apparent contradictions, a common link is a change in migratory
behaviour, either an arrest or a direction switch. Our results for the
hindbrain show that reelin intervenes where neurons change migration
direction. In conclusion, our data support the hypothesis that reelin acts as
a signal that renders neurons competent to change migration behaviour.
The lack of a reeler-like phenotype in the ApoER2/VLDLR mutants is
intriguing. In the neocortex and dentate gyrus, radial glial cells express
ApoER2/VLDLR receptors, and reelin is involved in radial glial process
elongation and maturation (Graus-Porta et
al., 2001; Hartfuss et al.,
2003
). ApoER2/VLDLR double mutants display a reeler-like
phenotype in the neocortex (Trommsdorff et
al., 1999
). We did not observe any major defect in radial glial
processes; although we cannot exclude that radial processes are affected in
the reeler hindbrain (e.g. by changes in brain lipid-binding protein
content), it seems unlikely that radial glial cells are the direct target of
reelin signaling in this case.
Yip et al. described recently the same phenotype as reeler in the
spinal cord of scrambler and ApoER2/VLDLR double mutants. However,
although ApoER2 and VLDLR expression is observed in preganglionic motoneurons
(Yip et al., 2004), we could
not correlate expression of these receptors with any of the affected nuclei in
the hindbrain. This suggests the involvement of another possible receptor,
such as integrins or CNRs. Analysis of CNR expression
(Carroll et al., 2001
) in the
hindbrain might fit with a potential receptor role for reelin, although their
capacity for Reln binding is still controversial
(Jossin et al., 2004
). ß1
integrin is another potential candidate
(Dulabon et al., 2000
) and
further investigation in this direction is necessary.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Auclair, F., Valdes, N. and Marchand, R. (1996). Rhombomere-specific origin of branchial and visceral motoneurons of the facial nerve in the rat embryo. J. Comp. Neurol. 369,451 -461.[CrossRef][Medline]
Beffert, U., Weeber, E. J., Morfini, G., Ko, J., Brady, S. T.,
Tsai, L. H., Sweatt, J. D. and Herz, J. (2004). Reelin
and cyclin-dependent kinase 5-dependent signals cooperate in regulating
neuronal migration and synaptic transmission. J.
Neurosci. 24,1897
-1906.
Bock, H. H. and Herz, J. (2003). Reelin activates SRC family tyrosine kinases in neurons. Curr. Biol. 13,18 -26.[CrossRef][Medline]
Bruce, L. L., Kingsley, J., Nichols, D. H. and Fritzsch, B. (1997). The development of vestibulocochlear efferents and cochlear afferents in mice. Int. J. Dev. Neurosci. 15,671 -692.[CrossRef][Medline]
Carroll, P., Gayet, O., Feuillet, C., Kallenbach, S., de Bovis, B., Dudley, K. and Alonso, S. (2001). Juxtaposition of CNR protocadherins and reelin expression in the developing spinal cord. Mol. Cell. Neurosci. 17,611 -623.[CrossRef][Medline]
Chandrasekhar, A. (2004). Turning heads: development of vertebrate branchiomotor neurons. Dev. Dyn. 229,143 -161.[CrossRef][Medline]
Cowan, C. A., Yokoyama, N., Bianchi, L. M., Henkemeyer, M. and Fritzsch, B. (2000). EphB2 guides axons at the midline and is necessary for normal vestibular function. Neuron 26,417 -430.[Medline]
D'Arcangelo, G., Miao, G. G., Chen, S. C., Soares, H. D., Morgan, J. I. and Curran, T. (1995). A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374,719 -723.[CrossRef][Medline]
Dulabon, L., Olson, E. C., Taglienti, M. G., Eisenhuth, S., McGrath, B., Walsh, C. A., Kreidberg, J. A. and Anton, E. S. (2000). Reelin binds alpha3beta1 integrin and inhibits neuronal migration. Neuron 27,33 -44.[Medline]
Fritzsch, B. (1999). Ontogenic and evolutionary evidence for the motoneuron nature of vestibular and cochlear efferents. In The Efferent Auditory System: Basic Science and Clinical Applications (ed., C. I. Berlin), pp.31 -59. San Diego: Singular Publishing.
Fritzsch, B. and Nichols, D. H. (1993). DiI reveals a prenatal arrival of efferents at the differentiating otocyst of mice. Hear. Res. 65,51 -60.[CrossRef][Medline]
Fujimoto, Y., Setsu, T., Ikeda, Y., Miwa, A., Okado, H. and Terashima, T. (1998). Ambiguus nucleus neurons innervating the abdominal esophagus are malpositioned in the reeler mouse. Brain Res. 811,156 -160.[CrossRef][Medline]
Garel, S., Garcia-Dominguez, M. and Charnay, P.
(2000). Control of the migratory pathway of facial branchiomotor
neurones. Development
127,5297
-5307.
Gavalas, A., Ruhrberg, C., Livet, J., Henderson, C. E. and
Krumlauf, R. (2003). Neuronal defects in the hindbrain of
Hoxa1, Hoxb1 and Hoxb2 mutants reflect regulatory interactions among these Hox
genes. Development 130,5663
-5679.
Goddard, J. M., Rossel, M., Manley, N. R. and Capecchi, M.
R. (1996). Mice with targeted disruption of Hoxb-1 fail to
form the motor nucleus of the VIIth nerve. Development
122,3217
-3228.
Goffinet, A. M. (1984). Abnormal development of the facial nerve nucleus in reeler mutant mice. J. Anat. 138,207 -215.[Medline]
Graus-Porta, D., Blaess, S., Senften, M., Littlewood-Evans, A., Damsky, C., Huang, Z., Orban, P., Klein, R., Schittny, J. C. and Muller, U. (2001). Beta1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex. Neuron 31,367 -379.[Medline]
Hack, I., Bancila, M., Loulier, K., Carroll, P. and Cremer, H. (2002). Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis. Nat. Neurosci. 5,939 -945.[CrossRef][Medline]
Hartfuss, E., Forster, E., Bock, H. H., Hack, M. A., Leprince,
P., Luque, J. M., Herz, J., Frotscher, M. and Gotz, M.
(2003). Reelin signaling directly affects radial glia morphology
and biochemical maturation. Development
130,4597
-4609.
Herz, J. and Bock, H. H. (2002). Lipoprotein receptors in the nervous system. Annu. Rev. Biochem. 71,405 -434.[CrossRef][Medline]
Hirotsune, S., Takahara, T., Sasaki, N., Hirose, K., Yoshiki, A., Ohashi, T., Kusakabe, M., Murakami, Y., Muramatsu, M., Watanabe, S. et al. (1995). The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons. Nat. Genet. 10,77 -83.[Medline]
Howell, B. W., Gertler, F. B. and Cooper, J. A.
(1997). Mouse disabled (mDab1): a Src binding protein implicated
in neuronal development. EMBO J.
16,121
-132.
Jossin, Y., Ignatova, N., Hiesberger, T., Herz, J., Lambert de
Rouvroit, C. and Goffinet, A. M. (2004). The central fragment
of Reelin, generated by proteolytic processing in vivo, is critical to its
function during cortical plate development. J.
Neurosci. 24,514
-521.
Karis, A., Pata, I., van Doorninck, J. H., Grosveld, F., de Zeeuw, C. I., de Caprona, D. and Fritzsch, B. (2001). Transcription factor GATA-3 alters pathway selection of olivocochlear neurons and affects morphogenesis of the ear. J. Comp. Neurol. 429,615 -630.[CrossRef][Medline]
Ko, J., Humbert, S., Bronson, R. T., Takahashi, S., Kulkarni, A.
B., Li, E. and Tsai, L. H. (2001). p35 and p39 are essential
for cyclin-dependent kinase 5 function during neurodevelopment. J.
Neurosci. 21,6758
-6771.
Kraus, F., Haenig, B. and Kispert, A. (2001). Cloning and expression analysis of the mouse T-box gene tbx20. Mech. Dev. 100,87 -91.[CrossRef][Medline]
Marin, O. and Rubenstein, J. L. (2003). Cell migration in the forebrain. Annu. Rev. Neurosci. 26,441 -483.[CrossRef][Medline]
Martin, M. R. (1981). Morphology of the cochlear nucleus of the normal and reeler mutant mouse. J. Comp. Neurol. 197,141 -152.[CrossRef][Medline]
Muller, M., Jabs, N., Lorke, D. E., Fritzsch, B. and Sander,
M. (2003). Nkx6.1 controls migration and axon pathfinding of
cranial branchio-motoneurons. Development
130,5815
-5826.
Ohshima, T., Ogawa, M., Takeuchi, K., Takahashi, S., Kulkarni,
A. B. and Mikoshiba, K. (2002). Cyclin-dependent
kinase 5/p35 contributes synergistically with Reelin/Dab1 to the positioning
of facial branchiomotor and inferior olive neurons in the developing mouse
hindbrain. J. Neurosci.
22,4036
-4044.
Pachnis, V., Mankoo, B. and Costantini, F.
(1993). Expression of the c-ret proto-oncogene during mouse
embryogenesis. Development
119,1005
-1017.
Pattyn, A., Morin, X., Cremer, H., Goridis, C. and Brunet, J.
F. (1997). Expression and interactions of the two closely
related homeobox genes Phox2a and Phox2b during neurogenesis.
Development 124,4065
-4075.
Pattyn, A., Hirsch, M., Goridis, C. and Brunet, J. F.
(2000). Control of hindbrain motor neuron differentiation by the
homeobox gene Phox2b. Development
127,1349
-1358.
Pattyn, A., Vallstedt, A., Dias, J. M., Sander, M. and Ericson,
J. (2003). Complementary roles for Nkx6 and Nkx2 class
proteins in the establishment of motoneuron identity in the hindbrain.
Development 130,4149
-4159.
Pfaff, S. L., Mendelsohn, M., Stewart, C. L., Edlund, T. and Jessell, T. M. (1996). Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell 84,309 -320.[Medline]
Phelps, P. E., Rich, R., Dupuy-Davies, S., Rios, Y. and Wong, T. (2002). Evidence for a cell-specific action of Reelin in the spinal cord. Dev. Biol. 244,180 -198.[CrossRef][Medline]
Poluch, S., Rossel, M. and Konig, N. (2003). AMPA-evoked ion influx is strongest in tangential neurons of the rat neocortical intermediate zone close to the front of the migratory stream. Dev. Dyn. 227,416 -421.[CrossRef][Medline]
Sharma, K., Sheng, H. Z., Lettieri, K., Li, H., Karavanov, A., Potter, S., Westphal, H. and Pfaff, S. L. (1998). LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons. Cell 95,817 -828.[Medline]
Sheldon, M., Rice, D. S., D'Arcangelo, G., Yoneshima, H., Nakajima, K., Mikoshiba, K., Howell, B. W., Cooper, J. A., Goldowitz, D. and Curran, T. (1997). Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature 389,730 -733.[CrossRef][Medline]
Simmons, D. D. (2002). Development of the inner ear efferent system across vertebrate species. J. Neurobiol. 53,228 -250.[CrossRef][Medline]
Singleton, C. D. and Casagrande, V. A. (1996). A reliable and sensitive method for fluorescent photoconversion. J. Neurosci. Methods 64,47 -54.[CrossRef][Medline]
Studer, M., Lumsden, A., Ariza-McNaughton, L., Bradley, A. and Krumlauf, R. (1996). Altered segmental identity and abnormal migration of motor neurons in mice lacking Hoxb-1. Nature 384,630 -634.[CrossRef][Medline]
Takahara, T., Ohsumi, T., Kuromitsu, J., Shibata, K., Sasaki,
N., Okazaki, Y., Shibata, H., Sato, S., Yoshiki, A., Kusakabe, M. et
al. (1996). Dysfunction of the Orleans reeler gene arising
from exon skipping due to transposition of a full-length copy of an active L1
sequence into the skipped exon. Hum. Mol. Genet.
5, 989-993.
Terashima, T., Kishimoto, Y. and Ochiishi, T. (1993). Musculotopic organization of the facial nucleus of the reeler mutant mouse. Brain Res. 617, 1-9.[CrossRef][Medline]
Terashima, T., Kishimoto, Y. and Ochiishi, T. (1994). Musculotopic organization in the motor trigeminal nucleus of the reeler mutant mouse. Brain Res. 666, 31-42.[CrossRef][Medline]
Tissir, F. and Goffinet, A. M. (2003). Reelin and brain development. Nat. Rev. Neurosci. 4, 496-505.[CrossRef][Medline]
Tiveron, M. C., Pattyn, A., Hirsch, M. R. and Brunet, J. F. (2003). Role of Phox2b and Mash1 in the generation of the vestibular efferent nucleus. Dev. Biol. 260, 46-57.[CrossRef][Medline]
Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A. and Herz, J. (1999). Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97,689 -701.[Medline]
Yip, Y. P., Capriotti, C., Magdaleno, S., Benhayon, D., Curran, T., Nakajima, K. and Yip, J. W. (2004). Components of the reelin signaling pathway are expressed in the spinal cord. J. Comp. Neurol. 470,210 -219.[CrossRef][Medline]