The amygdaloid complex is a group of nuclei that are thought to originate from multiple sites of the dorsal and ventral telencephalic
transcription factors that regulate regional specification and growth of the telencephalon, in the morphogenesis of the amygdaloid
olfactory tract and the lateral, basolateral, and basomedial nuclei, all appear to have a common requirement for Pax6. Together, our
epithelium is divided into domains that express distinct combi-
nations of transcription factors. This parcellation has provided a
mechanism for the specification of different telencephalic struc-
tral, the medial (MP), dorsal (DP), lateral (LP), and ventral pal-
domains. The ventral telencephalon contains the medial gangli-
as well as a region defined as the dorsal LGE (dLGE), which is
the pallium–subpallium boundary (PSB) and are proposed to
from the original domains in the neuroepithelium. These struc-
tures [the claustrum, endopiriform nucleus, amygdaloid com-
2000; Tamamaki et al., 2001; Gorski et al., 2002)] are the least
understood in terms of the mechanisms that control their speci-
fication and development.
Pax6 plays a significant regulatory role in dorsoventral pat-
terning (Stoykova et al., 1996, 2000), and mutations of this gene
affect the specification of the ventral pallium, which takes on a
subpallial identity (Stoykova et al., 2000; Yun et al., 2001). Fur-
tion (Chapouton et al., 1999). Previous studies have reported
defects in the formation of the piriform cortex, claustrum, en-
dopiriform nucleus, and anterior amygdala in Pax6 mutant
brains (Stoykova et al., 2000). These findings raised the hypoth-
esis that the amygdaloid complex, thought to arise in part from
the LP and VP, may be disrupted in the Pax6 mutant because of
either a specification defect or a migration defect.
2000) and that each is required for the graded expression of the
other: Pax6 and Emx2 inhibit the expression of each other, such
that in the Pax6 mutant, the Emx2 gradient is flattened out and
vice versa (Muzio et al., 2002; Muzio and Mallamachi, 2003).
Furthermore, Pax6 and Emx2 are suggested to act as het-
et al., 2002).
Studies of the roles of Pax6 and Emx2 to date have focused
subpallium boundary (Toresson et al., 2000; Yun et al., 2001).
Max-Planck Institute of Biophysical Chemistry, Am Fassberg, D-37077 Go ¨ttingen, Germany, E-mail:
TheJournalofNeuroscience,March9,2005 • 25(10):2753–2760 • 2753
This region is thought to contribute to the amygdaloid complex
(Smith-Fernandez et al., 1998; Puelles et al., 1999, 2000; Molnar
lateral telencephalon. Furthermore, we establish the expression
of these genes in the final locations of different amygdaloid nu-
clei. Finally, we examine the mechanisms involved in the devel-
opment of the amygdaloid complex.
A complete analysis of the development of the amygdala has
been hampered by a lack of markers for distinct amygdaloid nu-
Emx2, in the formation of specific amygdaloid nuclei, revealing
breeding facility. Pax6 and Emx2 mutant embryos were obtained by in-
tercrossing mice heterozygous for the Small eye mutant, Sey allele (Rob-
erts, 1967; Hogan et al., 1986) and heterozygous Emx2?/? mutants,
procedures followed Institute Animal Ethics Committee guidelines and
situ hybridization was performed as described previously (Bulchand et
al., 2003). Briefly, the hybridization was performed overnight at 70°C in
70°C in 2? SSC and 50% formamide and 1% SDS. Foster’s atlas (1998)
was used as a guide to the morphology of the embryonic amygdaloid
complex and for nomenclature as follows: anterior amygdaloid area
“nuclei”: anterior cortical (ACo); basolateral (BL); basomedial (BM);
terodorsal portion (MeD); Me, posteroventral portion (MeV); nucleus
of the lateral olfactory tract (nLOT).
via Axiovision software. False color overlays were made as in Yun et al.
(2001). Briefly, images of serial sections were “inverted” in Adobe Pho-
toshop (version 7.0; Adobe Systems, San Jose, CA) to give a white-on-
black picture, which was imported through either the red or green chan-
nels. These pseudocolored pictures were then overlaid.
As a starting point for our studies, we examined the expression
patterns of transcription factors in the lateral aspect of the em-
Pax6, Tbr1, Emx1, and Lhx2 have been reported to identify
prospective amygdalar regions (Puelles et al., 2000; Yun et al.,
2001; Medina et al., 2004). We examined the expression of some
of these markers together with that of Lhx9 and Emx2.
The first interesting feature of the gene expression patterns is
that there is an upregulation or downregulation of specific genes
mantle where streams of postmitotic cells are seen. Thus, three
transcription factors, Pax6, Emx2, and Lhx2, are expressed in the
ventricular zone in a continuous stretch in the region of the PSB.
The Pax6 domain includes the dLGE, whereas Lhx2 and Emx2
remain restricted to the pallial domains (Fig. 1a,c,g,i). In the ad-
jacent mantle, these and two other transcription factors, Lhx9
and Tbr1, identify streams of cells in a combinatorial manner as
follows. Pax6 expression is confined to a thin band of cells that
constitutes the dLGE (Puelles et al., 2000; Yun et al., 2001). This
stream extends toward the basal telencephalon, terminating at
the olfactory tuberculum (Puelles et al., 2000) (Fig. 1a,g).
LIM-HD transcription factor Lhx2 marks only the VP migrating
stream (Fig. 1c) (Yun et al., 2001). Similarly, the expression do-
that of Lhx2 (Fig. 1b,c). Both Lhx2- and Lhx9-expressing cells fall
sion is reported to be weak in the VP and in the adjacent LP and
strong in the more lateral DP (Puelles et al., 2000). When the
patterns of Pax6 or Tbr1 are overlaid with that of Lhx9, it is seen
to the Pax6-positive domain (Fig. 1e). That the Pax6-positive
domain is juxtaposed to but excludes the Tbr1/Lhx9-expressing
domain is further confirmed by two-color in situ hybridization,
Emx2 also identifies a stream of cells emerging from the PSB.
In adjacent sections from the same brain, it appears that Emx2
the migrating stream, whereas expression of Emx2 nearer the
ventricular zone is sparse (Fig. 1g–k). Emx2 expression, like that
of Lhx9, also appears perfectly complementary to that of Pax6
In summary, these results reveal a molecular parcellation
within the migratory streams in the basolateral telencephalon,
confirming and extending the previously reported schema
LP, which shows weak Tbr1 expression; then the VP, which is
positive for Tbr1 (weak), Lhx9, Lhx2, Emx2; and finally, a most
medial domain, the dLGE, a subpallial domain expressing only
To study which amygdalar structures might arise from the dLGE
and VP migrating streams observed at E12.5, we followed the
when amygdaloid nuclei are distinguishable in their final loca-
vations emerged. Pax6 and the VP stream markers Emx2, Lhx2,
trally, Pax6 intensely labels the AAD and the Ce (Fig. 2b). Emx2,
(Fig. 2c–e). Further caudally, Pax6 identifies the intercalated nu-
is consistent with the interpretation that this nucleus may be
partially subpallial in origin (Medina et al., 2004). Thus, similar
to stage E12.5, the expression of Pax6 and Emx2, Lhx2, and Lhx9
nuclei may arise from the corresponding migratory streams.
The nLOT is identified by intense expression of Tbr1 (Fig.
2a–e) (Medina et al., 2004). Pax6 and Emx2 do not label this
nucleus, whereas Lhx2 and Lhx9 are expressed only in layer 1 of
La, BL, and BM at more caudal levels (Puelles et al., 2000) (Fig.
2g). At this level of sectioning, the expression patterns of Emx2,
2754 • J.Neurosci.,March9,2005 • 25(10):2753–2760Toleetal.•Pax6andEmx2inAmygdalaDevelopment
Lhx2, and Lhx9 begin to diverge. Emx2 is expressed only in the
Me; Lhx9 is expressed in the BM and MeV; Lhx2 is weakly ex-
pressed in scattered cells in the BL and BM (Fig. 2i–k).
observed between the expression of molecular markers of the
onic amygdaloid nuclei. On the other hand, some of the expres-
sion patterns indicate that there is no simple correspondence
between the molecular parcellation within the ventricular zone,
the migrating streams at early stages, and the discrete structures
seen in the ventrolateral telencephalon at later embryonic stages.
Together, the data indicate an intricate upregulation and down-
opment of amygdaloid structures: in the ventricular zone, in the
migratory stream, and in the final location of the nucleus. This
the embryonic amygdala.
To explore the role of Pax6 and Emx2 in the development of the
amygdaloid complex, we examined Pax6?/? (Sey/Sey) and
Emx2?/? brains at two stages: first, at E12.5, the stage at which
molecularly distinct migrating streams are seen in the lateral tel-
encephalon, and at later stages (E15.5–E17.5), when distinct
Toleetal.•Pax6andEmx2inAmygdalaDevelopmentJ.Neurosci.,March9,2005 • 25(10):2753–2760 • 2755
amygdaloid nuclei can be identified. At
transcript. Consistent with previous re-
ports, Pax6 transcript expression is re-
duced in the neuroepithelium of the VP
more, the migrating stream emerging
from the dLGE is not apparent in the mu-
tant, suggesting that the cells fail to mi-
grate in the absence of Pax6 (Fig. 3a,e).
Strikingly, this defect appears limited to
the dLGE migrating stream. Lhx9, Emx2,
or Tbr1 expression identifies the VP and
ence of functional Pax6 in the neuroepithe-
lium of the VP and LP is not critical to gen-
At older stages, Sey/Sey mutants reveal
a disruption of several amygdaloid struc-
tures. Previous morphological analysis in-
dicated a severe dysgenesis of the amygda-
could not be distinguished (Stoykova et al., 2000). Here, we ex-
amine discrete anterior amygdaloid structures and basolateral
structures of the Sey/Sey mutant using specific markers at E17.5.
Starting with anterior structures, three independent markers,
NeuroD, a bHLH transcription factor, SCIP, a POU-domain tran-
scription factor, and LIM gene Lmo3, all mark the nLOT 2/3 in
control brains (Fig. 4a,b,d) (Remedios et al., 2004). These layers of
the nLOT appear to be missing in the Sey/Sey mutant (Fig. 4a,b,d).
Interestingly, the superficial layer of the nLOT (nLOT1), which ex-
of these structures in the Pax6 mutant. The labeled regions ap-
pear shrunken and also displaced toward the pial surface in the
mutant compared with the control (Fig. 4c).
which label the La and BL in control brains, are not detectable in
the corresponding regions of the Pax6 mutant brains, although
(Clim1a) and globus pallidus (Lmo3) appears normal (Fig. 5a,c).
The BM, ventral to the basolateral complex, appears drastically
E15.5 brains, the earliest stage at which specific marker expres-
2756 • J.Neurosci.,March9,2005 • 25(10):2753–2760 Toleetal.•Pax6andEmx2inAmygdalaDevelopment
sion is seen (Remedios et al., 2004). The basolateral complex is
missing at this age as well, and the basomedial nucleus also ap-
pears extremely reduced (Fig. 5e,f).
tures within the amygdaloid complex appear relatively less af-
fected in the Pax6 mutant. Clim1a expression in the MeD and
MeV is seen in the appropriate locations in control and mutant
brains (Fig. 5b). This indicates that the specification and mor-
phological formation of these nuclei do not require Pax6. The
small reduction in size of these nuclei is consistent with the
slightly smaller size of the Pax6 mutant brain compared with
Using the same set of markers, we examined the effect of loss
of function of transcription factor Emx2 in developing
Emx2?/? embryos. Surprisingly, no detectable perturbation of
the amygdaloid complex was seen. At E17.5, the mutant nLOT
expresses Lmo3 in layers 2/3, whereas Lhx9 expression is seen in
layer 1, as in the control (Fig. 6a,c). Lhx9 is also expressed in the
mutant and control ACo and AAV (Fig. 6c). The mutant La and
BL both strongly express Lmo3 (Fig. 6b); the BM expresses Lhx9
strongly, whereas the MeV shows weaker Lhx9 expression, as in
controls (Fig. 6d).
It is generally accepted that the amygdalar structures originate
located at the junction of the dorsal and ventral telencephalon.
Several authors have reported streams of cells that arise from the
pathway, accumulations of cells named the “head” and the “res-
ervoir” have been identified by Bayer et al. (1991), from which
cells migrate and contribute to formaiton of the piriform cortex
the La, BL, and BM amygdaloid nuclei are
pallial in origin, arising from the VP and
LP, respectively (Puelles et al., 2000; Me-
dina et al., 2004); however, the migrating
streams from each of these domains have
yet to be definitively fate mapped.
Several transcription factors are impli-
cated in cell-fate specification in the telen-
lective regional defects or perturb specific
processes such as migration (Wilson and
Rubenstein, 2000). Analysis of the effects
of these mutations on amygdaloid devel-
opment has not been possible because of a
dearth of markers that identify the various
amygdaloid nuclei. Furthermore, several
patterning-defective mutants die in em-
possible roles in the development of this
structure more difficult. We used a newly
established set of markers that selectively
label amygdaloid nuclei in embryonic
stages (Remedios et al., 2004) to evaluate
the roles of two important players in dor-
soventral telencephalic patterning, Pax6
and Emx2, in the development of this
The genes Pax6 and Emx2, encoding
homeodomain transcription factors, have
cal fate and suppressors of subpallial fate
lium. Loss of function of either of these genes causes severe and
complementary defects in cortical area specification, consistent
esized that Pax6 and Emx2 also regulate the development of the
amygdala, because it is a complex structure consisting of numer-
ous nuclei extending in a large rostrocaudal domain within the
of amygdaloid nuclei are missing or extremely reduced. In con-
the VZ or during migration of the cells. Second, the structures
disrupted in the Pax6 mutant include nuclei from different sub-
groups: the nLOT, together with the ACo, are thought to be ol-
factory structures and considered to be part of the olfactory cor-
tex, a pallial derivative, although their precise neuroepithelial
origin is not known (Swanson and Petrovich, 1998). The La, BL,
and BM are thought to be part of a different pallial amygdaloid
subgroup, arising from the VP and LP (Puelles et al., 2000; Me-
dina et al., 2004). Not much is known about the origin or affilia-
origin, whereas the medial and central nuclei form the “subpal-
lial” group (Swanson and Petrovich, 1998; Medina et al., 2004).
Our findings suggest a common requirement for Pax6 across
subgroups, raising the possibility of multiple roles for Pax6 after
subgroup identity has been allocated. Finally, in the cortex, Pax6
and Emx2 mutant phenotypes exhibit a complementarity that is
Toleetal.•Pax6andEmx2inAmygdalaDevelopment J.Neurosci.,March9,2005 • 25(10):2753–2760 • 2757
the amygdala, however, we found no such complementary phe-
notypes, suggesting that the cooperative actions of Pax6 and
Emx2 in this complex may be quite different from those in the
cortex. These issues will be discussed in detail below.
Although Pax6 expression in the wild-type E12.5 telencepha-
lon is present in the ventricular zone of dLGE, VP, and LP and
also in the dLGE migratory stream, it is not detectable at later
BL, or BM. Therefore, Pax6 must function at earlier stages in
these cells, either during the specification of these cells in the
ventricular zone or during their migration. That the lateral mi-
gratory stream is defective in the absence of Pax6 has been noted
defective migration in the absence of Pax6, these mutants also
cell adhesion molecule, and R-cadherin (Caric et al., 1997;
a failure of the cells to migrate to their correct positions and
assemble into morphologically recognizable structures. This sce-
nario of a migration defect would imply that these cells are spec-
ified correctly but would be mislocated to the pial surface if they
have over-migrated or may be found near their origins at the
ventricular zone if they have under-migrated; however, using
several independent markers, we detected no such mislocated
cells. These observations indicate that the primary defect in the
Pax6 mutant amygdala is that of specification or proliferation of
the precursors that will contribute to specific amygdaloid nuclei.
There is as yet no good understanding of where and when the
trast to the cortex, in which layer-specific identity is known to be
established in the ventricular zone (McConnell and Kaznowski,
1991); however, there are some indications of the origins of dif-
ferent nuclei. One suggestion is that at very rostral levels, the
Pax6-positive dLGE stream may contribute to the formation of
the olfactory tubercle, the nucleus accumbens, and the primor-
dium of the anterior olfactory nucleus (Puelles et al., 2000). Fur-
thermore, the rostral VP neuroepithelium has been proposed to
be the site of origin of the ventromedial claustrum, La, endopiri-
form nucleus, and ACo (Puelles et al., 2000; Medina et al., 2004).
brain (Stoykova et al., 2000). It is striking that Pax6 expression
levels are highest in the rostrolateral neuroepithelium (Bishop et
al., 2000; Stoykova et al., 2000), a region that includes the rostral
VP and dLGE domains. Our findings of severe disruptions in the
nLOT2/3, La, and BL of Sey/Sey mutants suggest that high Pax6-
in the absence of Pax6. In contrast, we find the BM to be less
severely affected (shrunken, but not missing) in the absence of
Pax6. This nucleus is thought to arise from the caudal VP (Me-
dina et al., 2004), a region of low Pax6 expression (Bishop et al.,
2000). Similarly, the Me is thought to arise from the VZ of the
weak phenotype. Indeed, we find normal morphology and
marker expression in the MeD and MeV. In summary, similar to
the lateral cortex (Stoykova et al., 2000; Yun et al., 2001) and the
spinal cord (Burrill et al., 1997; Ericson et al., 1997), the severity
of the Pax6 mutant phenotype within the amygdaloid complex
appears to depend on the level of Pax6 expression in the neuro-
epithelial domain from which the different structures arise.
Striking specification defects in the neuroepithelium of the
Pax6 mutant were reported previously; a general feature of the
Pax6 phenotype was a dorsal shift of subpallial markers
(Stoykova et al., 2000; Toresson et al., 2000, Yun et al., 2001). In
particular, the expression of genes normally restricted to the
expression of Clim1a (a) and Lmo3 (c) display expression in the La (arrow) and the BL (open
greatly reduced BM in the mutant (f, notched arrowhead). In contrast, both portions of the
2758 • J.Neurosci.,March9,2005 • 25(10):2753–2760 Toleetal.•Pax6andEmx2inAmygdalaDevelopment
MGE, Nxk2.1, and shh spreads into the LGE (Stoykova et al.,
cells, because the shh expression domain has spread laterally. A
more fundamental cause, however, seems to be a specification
defect of the neuroepithelium. Several studies indicate that the
dLGE, together with the VP and LP, shows the strongest pheno-
type in the absence of functional Pax6: Mash1, Dlx1,2, and Gsh2,
Tbr1, and Lhx2 are almost eliminated at the PSB (Stoykova et al.,
1996, 2000; Toresson et al., 2000; Yun et al., 2001; Muzio et al.,
2002). Rather than being shifted dorsally, the VP in the Pax6
mutant appears to be defective, based on the absence of VP-
specific markers sFrp2 and Dbx1 (Kim et al., 2001; Yun et al.,
2001; Assimacopoulos et al., 2003). A deficient VP in the Tlx
mutant has been correlated with disrupted La and BL develop-
ment (Stenman et al., 2003).
Our report that the Pax6 mutant dLGE fails to generate a
migrating stream of cells at E12.5 places this structure in an im-
together with the VP and LP. Interestingly, although the dLGE is
a subpallial structure, it appears not to contribute to the Me and
AAV, both of which are present in the Pax6 mutant. This raises
of the “pallial” nuclei nLOT2/3, La, BL, and BM. Pax6 may func-
tion in the VZ of the dLGE, VP, and LP to regulate specification
and/or proliferation of the cells that will populate the nLOT2/3,
La, BL, and BM. Finally, this is the first report of distinct regula-
tory mechanisms underlying the formation of different layers of
an amygdaloid nucleus, the nLOT, such that layers 2/3 require
Pax6 function but layer 1 is Pax6 independent.
In striking contrast to the disrupted amygdaloid complex in
the Emx2 mutant. In the cortex, the loss of Emx2 causes a dra-
matic shift in area boundaries (Bishop et al., 2002) and a disrup-
tion of hippocampal morphogenesis (Tole et al., 2000), whereas
amygdaloid development. This may be because of redundancy
An alternative hypothesis for the apparently normal Emx2
mutant amygdala is based on the levels of expression of Emx2 in
the PSB region. Although Pax6 is expressed in a high rostrolat-
eral, low caudomedial gradient, Emx2 has a complementary ex-
pression (Bishop et al., 2000). Each of these mutations may dis-
play the strongest phenotype in regions where the gene is most
highly expressed. Consistent with this idea, it is the medial-most
structure of the hippocampus, the dentate gyrus, that displays a
strong morphological disruption in the absence of Emx2 (Pelle-
grini et al., 1996; Yoshida et al., 1997; Tole et al., 2000). The PSB
is a region of low Emx2 expression, which may explain why its
derivatives are spared in the mutant. In contrast, for Pax6, the
phenotypes may be expected to correlate with its level of expres-
sion in the rostral versus the caudal PSB domains, as has been
In summary, our findings reveal no complementarity in the
amygdalar phenotype between the Pax6 and Emx2 mutants, in-
dicating that any interplay between Pax6 and Emx2 in the speci-
fication of the amygdaloid complex is likely to be different from
their interactions in regulating regional domains within the VZ.
Additional studies will examine whether the amygdaloid pheno-
copies of Emx2. This will test for a cooperative role between the
two molecules, as has been shown in the cortical primordium
(Bishop et al., 2000). In addition, Pax6 is known to cooperate
with other molecules such as Gsh2 and Tlx in specifying the pal-
2003), and these interactions may also play a role in the develop-
ment of the amygdaloid complex. This study used a panel of
markers that will be a useful tool for analyzing these questions
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