Diminished dosage of 22q11 genes disrupts
neurogenesis and cortical development in a mouse
model of 22q11 deletion/DiGeorge syndrome
Daniel W. Meechana, Eric S. Tuckera, Thomas M. Maynarda, and Anthony-Samuel LaMantiaa,b,1
aDepartment of Cell and Molecular Physiology andbNeuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599
Edited by Pasko Rakic, Yale University School of Medicine, New Haven, CT, and approved July 22, 2009 (received for review May 28, 2009)
The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of
connectivity’’ thought to arise during development, including schizo-
phrenia and autism. We show that diminished dosage of the genes
deleted in the 1.5-megabase 22q11 minimal critical deleted region in
a mouse model of 22q11DS specifically compromises neurogenesis
basal, but not apical, progenitors is disrupted, and subsequently, the
This change is paralleled by aberrant distribution of parvalbumin-
labeled interneurons in upper and lower cortical layers. Deletion of
Tbx1 or Prodh (22q11 genes independently associated with 22q11DS
phenotypes) does not similarly disrupt basal progenitors. However,
expression analysis implicates additional 22q11 genes that are selec-
tively expressed in cortical precursors. Thus, diminished 22q11 gene
dosage disrupts cortical neurogenesis and interneuron migration.
Such developmental disruption may alter cortical circuitry and estab-
lish vulnerability for developmental disorders, including schizophre-
nia and autism.
cortical development underlies behavioral pathology. Despite in-
ferred relationships between suspect developmental mechanisms,
cortical pathology, to our knowledge, there are no known direct
links between specific cortical developmental mechanisms and
pathogenesis. The near impossibility of prospective analyses in
hypothesis. Thus, the hypothesis may be more effectively evaluated
in animal models of genetic or environmental risk for relevant
diseases. In humans, 22q11 deletion/DiGeorge syndrome
(?30%) (3, 4), increased susceptibility for autism spectrum disor-
ders (?25%) (5), and vulnerability for additional behavioral and
shows consistent anatomical defects, including reduced cortical
gray matter and polymicrogyria (6–8), and postmortem analysis
indicates cellular pathology associated with developmental defects
including periventricular heteropias (9). We found that diminished
22q11 gene dosage in a 22q11DS mouse model compromises
specific cortical neural stem cells, basal progenitors, and alters
frequency and distribution of cortical projection neurons and
GABAergic interneurons. These phenotypes suggest a link be-
tween a genomic lesion, altered cortical development, and subse-
quent changes in cortical circuitry that likely intensify risk for
behavioral disorders in 22q11DS patients.
he neurodevelopmental hypothesis for diseases of cortical
connectivity, initially proposed for schizophrenia (1), and later
Diminished Dosage of 22q11 Genes Disrupts Basal Progenitor Prolif-
eration. We first asked, using the LgDel mouse model of
22q11DS (10), whether 22q11DS cortical anomalies might re-
flect changes in cortical neurogenesis. We focused on two
distinct classes of cortical progenitors: basal progenitors–transit
amplifying progenitors in the cortical subventricular zone
(SVZ)–and apical progenitors–self-renewing radial glial stem
cells present in the cortical VZ. Each class can be recognized
with combinations of proliferative and molecular markers (Fig.
1). We found reduced frequency of mitotic basal progenitors,
identified by phosphohistone 3 labeling (PH3; a G2/M-phase
cell-cycle marker) as well as SVZ location, throughout the
embryonic day (E)13.5 LgDel cortex (79% of WT, P ? 0.05, n ?
5 per genotype) (Fig. 1 A–C; Fig. S1). Analysis of dual BrdU
(90-min exposure; S-phase marker) and Tbr2 labeling (basal
progenitors) confirms this deficit (76% of WT, t test, P ? 0.049,
n ? 5) (Fig. 1 D–F). When systematically sampled at dorsal,
medial, and lateral cortical locations, LgDel S-phase basal
progenitor frequency was diminished by 32% in medial cortex
(n ? 5; t test, P ? 0.045) (Fig. 1F Middle), 20% laterally
(nonsignificant), and similar to normal dorsally.
Aberrant apical progenitor proliferation or radial migration is
not the basis for the basal progenitor proliferation defect. There
are comparable numbers of S-phase apical progenitors in LgDel
and littermate controls at each cortical site (Fig. 1F Bottom).
Also, apical progenitors generate basal progenitors at similar
frequencies in each genotype (Fig. 1 G–I). Furthermore, apical
progenitor radial processes, on which nascent basal progenitors
as well as newborn neurons migrate, seem unperturbed in the
mutant (Fig. 1J).
Of the 22 22q11 genes expressed in the developing cerebral
cortex (11), two genes (Tbx1 and Prodh) have emerged as candi-
dates for many 22q11DS phenotypes, including behavioral anom-
alies (12, 13). Nevertheless, we found no differences in basal
progenitor frequency in either hemizygous Tbx1 or homozygous
Prodh hypomorphic mice (Fig. 1 C and F) (embryonic gene
is unlikely to explain the proliferative phenotype associated with
hemizygous 22q11 deletion.
A Subset of 22q11 Genes Is Associated with the Cortical Proliferative
Zone. We asked whether other genes in the 22q11 region might
contribute to apparent disruption of cortical basal progenitor
proliferation in the LgDel mouse. We evaluated candidates by
noting their putative cell-cycle function, selective expression in the
cortical VZ/SVZ, and maximal expression during neurogenesis.
Cdc45l (15), Hira (16), Ufd1l (17), and Sept5 (18); a sixth gene with
Author contributions: D.W.M., E.S.T., T.M.M., and A.-S.L. designed research; D.W.M. and
E.S.T. performed research; T.M.M. contributed new reagents/analytic tools; D.W.M. and
A.-S.L. analyzed data; and D.W.M. and A.-S.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1To whom correspondence should be addressed. E-mail: firstname.lastname@example.org.
This article contains supporting information online at www.pnas.org/cgi/content/full/
September 22, 2009 ?
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unknown function, Htf9c, shares a promoter with Ranbp1 (19), and
thus, was also analyzed. Ranbp1 and Cdc45l are specifically and
are enhanced in the VZ/SVZ and developing cortical plate (Fig. 2
C and D). Hira is weakly present throughout the developing cortex
(Fig. 2E). Last, Sept5 is absent from the VZ/SVZ, instead localized
are maximally expressed during cortical neurogenesis [E12-
postnatal day (P)0] with a large decline thereafter (Fig. S3). In
contrast, there is stability (Ufd1l), modest transient increase (Hira),
or significant, sustained increase (Sept5) of the other genes (Fig.
S3). Thus, expression localization, dynamics, and established cell-
cycle function suggest candidate 22q11 genes for the basal progen-
Altered Expression of Cell-Cycle Genes in the LgDel Cortex. We next
asked whether expression of these six 22q11 genes or other genes
beyond the 22q11 interval is diminished in the embryonic LgDel
mouse cortex. Expression of all six 22q11 genes is diminished by
?50% in E13.5 LgDel cortex (Fig. 3A). Diminished cortical ex-
pression of these 22q11 genes, as well as altered basal progenitor
proliferation, suggests there may be further changes in cell-cycle
regulatory genes beyond the 22q11 region. We probed a cell-cycle
specific array (SABiosciences) with cDNA from E13.5 LgDel and
WT cortex. We found and confirmed reduced expression in LgDel
cortex of 3/84 array genes (Fig. 3B): Cyclin D1, a key component of
the G1/S cell-cycle transition (20, 21); E2f2, involved in S-phase
progression (20); and Sestrin2, thought to regulate proliferation in
response to cellular stress (22). Local expression of each protein is
sometimes in combination with the 22q11 protein, Cdc45l (Fig. 3
C–E). Thus, expression of cell-cycle regulatory genes beyond the
22q11 region is disrupted in the cortical VZ/SVZ in concert with
aberrant basal progenitor proliferation.
Altered Layer 2–4 Neurons in the Maturing LgDel Cortex. Basal
progenitors give rise primarily to layer 2–4 projection neurons.
Therefore, diminished proliferation of these cells in the embryonic
LgDel cortex might be accompanied by changes in neuronal
composition of the supragranular cortical layers at later ages. Thus,
we determined the frequency of supra- and infragranular cortical
neurons in P5 LgDel cortex. Using a pan-neuronal marker, NeuN,
we found no significant change in the total frequency of neurons
located in radial probes systematically located at lateral, medial, or
dorsal cortical sites (Fig. 4 A and B). However, there was a trend
toward diminished NeuN cell frequency in the medial probe
location. Therefore, we determined NeuN cell frequency at this
location in 10 equivalent bins between the pial surface and white
matter. We found reduced NeuN cell frequencies in the medial
supragranular LgDel cortex (Fig. 4C). We further evaluated the
representation showing that basal and apical progenitors, both labeled by PH3, are discerned by their positions in the SVZ versus VZ (Right). (B) PH3 immunolabeling
in the E13.5 cortex of WT and Large Deletion mice (LgDel) (10). (C) PH3 labeled cell frequency in the SVZ throughout its entire lateral to dorsal extent is significantly
cells, throughout the entire cortex, are more frequent in WT versus LgDel (*, P ? 0.05). However, their frequency is not changed in Prodh?/?or Tbx1?/?(Top). There
is a significant decrease of Tbr2?/BrdU? cells in the medial and a trend in the lateral E13.5 LgDel cortex (Middle). Tbr2-/BrdU? cell frequency is unchanged at all WT
enough time for a fraction of labeled apical progenitor progeny to migrate toward the SVZ, and express Tbr2. Concurrently, BrdU-labeled basal progenitors
down-regulate Tbr2 and migrate toward the cortical plate. The fraction of BrdU? cells that are also Tbr2? reflect basal progenitor generation by apical progenitors
(54). (H) Tbr2?/16 h BrdU? cells (yellow) in WT and LgDel E13.5 cortex. (I) Apical progenitor genesis of basal progenitors (Tbr2?BrdU/BrdU cells) is not significantly
neuroblasts (Dcx, doublecortin) or radial glial processes (nestin) (arrowheads).
Diminished 22q11 gene dosage disrupts cortical basal progenitor proliferation. (A) Schematic representation of a coronal section through the mouse E13.5
Meechan et al.PNAS ?
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laminar specificity of this change using markers for molecularly
distinct cortical neurons. There was a 20% decrease in the fre-
quency of neurons labeled for Cux1, a layer 2–4 selective marker
(23), in the medial LgDel cortex (n ? 5 per genotype; t test, P ?
0.02) (Fig. 4D). In contrast, the frequency of neurons labeled for
Cux1 neuron frequency is unchanged at all cortical sites in Tbx1?/?
mice and Prodh?/?deficient mice (data not shown).
To determine whether this specific change in layer 2–4
neuron frequencies reflects altered basal progenitor prolifer-
ation at E13.5 (Fig. 1), we analyzed the frequency of E13.5
birth-dated Cux1 or Tbr1 neurons in the P5 cortex. The
frequency of E13.5 BrdU birth-dated/Cux1 double-labeled
neurons was diminished by 50% only at the medial location
(n ? 4 LgDel, n ? 5 WT; P ? 0.01) (Fig. 4E). However, there
was no significant difference in E13.5 BrdU injected/Tbr1
labeled layer 5/6 cells (Fig. S4). There was no evidence of
compensation by accelerated neurogenesis later in develop-
ment. We found no significant difference in E18.5 BrdU/Cux1
cell frequency between genotypes (Fig. 4E). Last, we did not
see prolonged neurogenesis. E19.5 birth-dated neurons
were not present in LgDel or WT P5 cortex (data not shown).
Apparently, proliferative changes in E13.5 basal pro-
genitors prefigure a corresponding change in the frequency of
supragranular projection neurons in the medial cortex of
neurogenesis. In all images, the entire cortical hemisphere from an E14.5 WT
embryo is shown (Left), whereas higher magnification of VZ, intermediate
zone (IZ), and cortical plate (CP) is shown (Right). ISH shows that 22q11
cell-cycle genes are enhanced in the VZ [Ranbp1 (A); Cdc45l (B)] enhanced in
both the VZ and CP [Htf9c (C); Ufd1l (D)] lightly, but broadly expressed [Hira
(E)] or enhanced in the CP [Sept5 (F)].
Expression localization of 22q11 cell-cycle genes during cortical
Six 22q11 putative cell-cycle genes show diminished expression by ?50% (*,
P ? 0.05;**, P ? 0.001) relative to WT E13.5 cortex. (B) Quantitative PCR
verifies that three cell-cycle gene transcripts are diminished by ?50% (*, P ?
Protein products of these three genes are detected in cells that also express
Cdc45l, PH3, or Tbr2. (C) Sestrin2 (Left), colabeled with Cd45l (Center), or PH3
(Right). (D) CyclinD1 in E13.5 cortex (Left), colabeled with Cdc45l (Center), or
Tbr2 (Right). (E) E2f2 in E13.5 cortex (Left), colabeled with Cdc45l (Center),
or Tbr2 (Right).
Changes in cell-cycle gene expression in embryonic LgDel cortex. (A)
www.pnas.org?cgi?doi?10.1073?pnas.0905696106 Meechan et al.
Altered Distribution of Interneurons in the LgDel Cortex. Changes in
with schizophrenia and other disorders of cortical connectivity
(25, 26). Thus, we analyzed the distribution of parvalbumin-
labeled interneurons, a proposed target for pathologic change
(25, 26), in the LgDel postnatal cortex. There was no significant
difference in parvalbumin cell frequency at P21. Nevertheless,
their laminar distribution changes in the medial, but not lateral
or dorsal cortex (two-way ANOVA, P ? 0.03, n ? 5 per
genotype) (Fig. 5 A and B). We asked whether this change
reflects altered migration of embryonic GABAergic neuro-
blasts. Parvalbumin is not expressed in mouse cortex until the
second postnatal week (27). Therefore, we labeled the embry-
onic GABAergic cohort with calbindin (Fig. 5C), which is
expressed in migrating interneurons (28). The frequency of
calbindin-labeled cells did not differ in the two genotypes at
E13.5. However, their distribution from the corticostriatal
boundary to the cortical hem was altered in LgDel embryos
(two-way ANOVA, P ? 0.05, n ? 5 per genotype) (Fig. 5E). The
proportion of calbindin labeled cells in progressively medial
locations diminishes more rapidly (Fig. 5 D and E), suggesting
disrupted or delayed interneuron migration in the embryonic
schizophrenia, autism, and other behavioral disorders disrupts
neurogenesis as well as frequency and distribution of projection
neurons and migration of interneurons in a restricted region of
the cerebral cortex. Our results suggest local changes in gray
matter and neuropil, deduced from imaging and pathological
assessment in 22q11DS patients (6–9), may reflect altered
identity, abundance, and connections of projection neuron
disrupted basal progenitor proliferation. (A) Schematic representation of probe
and layer 5/6 (Tbr1) cortical neurons in the WT and LgDel cortex at P5. (C) NeuN
at LgDel bins 2 and 3 (*, P ? 0.05), which include supragranular cortical layers
(layer 2–4). (D) Layer 2–4 neurons double-labeled for NeuN and Cux1 in P5 WT
and LgDel cortex (Left). Layer 5/6 neurons double-labeled for NeuN and Tbr1 in
P5 WT and LgDel cortex (Right). There is a significant decrease in Cux1 labeled
mutant (Upper;*, P ? 0.05) Tbr1 cells are not significantly altered at any cortical
location (Lower). (E) Layer 2–4 neurons in P5 mouse cortex BrdU birth-dated at
E13.5 (Left) and E18.5 (Right) and double-labeled for Cux1. There is a significant
decrease in frequency of E13.5 generated Cux1 neurons only at the medial
location in the LgDel cortex (Upper;**, P ? 0.01). There is no significant differ-
ence in E18.5 generated Cux1 cells (Lower; ND, not detected). D, dorsal; DM,
dorsomedial; M, medial; ML, mediolateral; L, lateral.
Altered frequency of supragranular projection neurons accompanies
labeling for parvalbumin in P21 WT and LgDel cortex (medial probe) shows
altered location of cells in the LgDel cortex. (B) Parvalbumin cell distribution
across 10 equivalent bins from pia to white matter in WT and LgDel P21 cortex.
was observed between genotype and bin location medially (two-way ANOVA,
P ? 0.03, n ? 5 per genotype). LSD test records a significant difference in
migrating interneurons in E13.5 WT and LgDel cortex. White lines mark bin
from the corticostriatal boundary to cortical hem and calbindin cell numbers in
each bin determined. (E) The distribution of calbindin cells across five bins in
LgDel and WT E13.5 cortex. Genotype has a significant effect on calbindin cell
distribution (two-way ANOVA,*, P ? 0.05, n ? 5 per genotype). A significant
difference in calbindin frequency between genotypes at bin 3 was seen (LSD;*,
P ? 0.05).
Interneuron distribution is disrupted in the LgDel cortex. (A) Immuno-
Meechan et al.PNAS ?
September 22, 2009 ?
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classes due to disrupted basal progenitor proliferation, and
parallel changes in interneuron migration and placement during
development. These phenotypes provide support for the neuro-
developmental hypotheses of disorders of cortical connectivity
associated with 22q11DS.
The basal progenitor deficit in the LgDel model of 22q11DS
apparently leads to altered frequency of supragranular neurons
later in life. Basal progenitors may generate projection neurons for
all cortical layers (29). Nevertheless, several observations suggest
that they give rise primarily to supragranular pyramidal cells (30).
Such projection neurons, present in altered numbers in LgDel
cortex, may fail to elaborate appropriate local and long distance
projections. The resulting disruptions in circuitry may lead to
pathological changes, including altered interneuron distribution
and frequency, as well as altered projection neuron connection in
diseases of cortical connectivity that accompany 22q11DS (31–33).
In contrast, apical progenitors are spared. Their ability to generate
basal progenitors is unimpaired; their capacity to support radial
migration is not noticeably altered, and their primary neuronal
progeny (infragranular projection neurons) do not seem affected.
Thus, our results identify a specific cortical progenitor class as a
target for pathologic change, and specific cortical layers as subse-
quent loci for potentially altered circuitry in 22q11DS.
These alterations in the 22q11DS mouse model are restricted to
medial cortical regions. Regionally selective basal progenitor and
supragranular neurons deficits may reflect divergent activity of
local signals and transcription factors (34). 22q11 genes may nor-
the context of regional signals, resulting in appropriate local dif-
ferences in cortical thickness, surface area, and gyral patterns (35).
At present, one postmortem study of three 22q11DS schizophrenic
brains (9) and a limited number of global MRI studies in 22q11DS
patients (6–8) have been completed. The periventricular hetero-
topias and subtle differences in cortical thickness and gyral com-
plexity in frontal and temporal cortical regions are generally
consistent with region-selective developmental changes. Anterior
frontal motor/association areas (36) appear most compromised in
LgDel mice; nevertheless, it is difficult to predict cortical regions
that might be similarly altered in 22q11DS patients.
Secondary effects due to cardiovascular phenotypes associated
with Tbx1 (10, 37) or metabolic deficiency due to mitochondrial
Prodh function (38, 39) do not appear to compromise basal
progenitor proliferation and cortical development independent of
other 22q11 genes. A recent study indicates that congenital heart
defects may contribute to cortical anomalies in 22q11DS (40).
However, the largest defects in cortical gyral patterns are indepen-
dent of cardiovascular malformations. Thus, our results are con-
between brain and cardiovascular phenotypes in 22q11DS. Never-
theless, additional 22q11 genes that influence either cardiovascular
development or metabolic function (41, 42) may secondarily con-
tribute to cortical phenotypes in 22q11DS.
Recent evidence suggests that at least two 22q11 genes,
Zddhc8 (43) and Dgcr8 (44), can compromise forebrain cir-
cuitry, particularly in the hippocampus. Our data suggests
additional candidates (particularly Ranbp1 and Cdc45l) as
potential contributors to altered cortical development in
22q11DS. RANBP1 polymorphisms have been associated with
schizophrenia vulnerability in non-22q11 deleted individuals
(45) and restricted CDC45L, as well as UFD1L, deletion has
been associated with 22q11DS clinical features including
heart, craniofacial, and thymic anomalies (42). The cell-cycle
functions of both Ranbp1 and Cdc45l, their diminished ex-
pression in LgDel VZ/SVZ, and parallel diminished expression
of CyclinD1 and E2f2, major regulators of the G1/S check
point, indicate that local activity of 22q11 genes may influence
cortical cell-cycle dynamics. This influence may extend beyond
cortical development. These genes continue to be expressed in
adult forebrain neurons and precursors (11), and may be part
of larger cell-cycle regulatory networks that are differentially
disrupted in schizophrenic and bipolar patients (46). Last,
altered cell-cycle control in cortical precursors due to dimin-
ished 22q11 gene dosage may also contribute to increased
tumorigenesis in 22q11 patients (47).
There are several potential explanations for altered placement,
but not frequency, of parvalbumin interneurons, the most numer-
ous cortical interneuron subtype (48), most often associated with
pathology in disorders of cortical connectivity (25, 26). Diminished
22q11 gene dosage may disrupt interneuron specification in the
medial ganglionic eminence, where most of these cells are gener-
ated, or their migration to the cortex. Such changes may compro-
mise the ability of subsets of interneurons to recognize appropriate
regional or laminar positions. Alternately, altered migratory inter-
neurons might perturb basal progenitor integrity (49) due to the
close proximity of these cell types; thus, disrupting subsequent
cortical proliferation as well as projection neuron and interneuron
distribution. Last, changes in interneuron migration or distribution
may reflect disrupted basal progenitor proliferation. Basal progen-
itors secrete chemoattractants for migrating interneurons (50), and
diminished numbers in medial cortical regions may make them less
effective migratory targets.
Altered placement of interneurons, as well as frequency of layer
2–4 projection neurons due to diminished 22q11 gene dosage, may
establish vulnerability for any of several behavioral disorders asso-
ciated with 22q11DS (3–5). Although our observations are unlikely
to provide a singular explanation for the range of psychiatric illness
defects establish a likely contributor to circuit vulnerability (and
behavioral disturbances) in the LgDel mouse model of 22q11DS
(51), and provide some guidance for subsequent analyses of brain
abnormalities in 22q11DS.
Materials and Methods
Experimental Animals. Mice carrying a hemizygous deletion from Idd to Hira
(C57BL/6J) contains a base substitution that reduces, but not abolishes Prodh
function (13). The Tbx1 line (129S) replaces Tbx1 with a neomycin cassette
deleting all but the first 22 aa (52). Animal procedures met the University of
North Carolina, Chapel Hill Institutional Animal Care and Use Committee
RNA Isolation, cDNA Synthesis, and qPCR. Tissues were dissected and homoge-
green reagent (Applied Biosystems), with 200 ?M forward and reverse primer,
was used to amplify cDNA using the ABI 7500 system.
PBS and immersion-fixed overnight in 4% paraformaldehyde (PFA). Postnatal
animals were perfused through the heart with 4% PFA after anesthetization
(urethane 2 mg/kg). Fixed brains were sectioned and stained as described previ-
ously (11). Primary antibodies are listed in Table S2. For fluorescent detection,
To generate a novel avian anti-Cdc45l antibody, chickens were immunized with
tested by Western blotting (Aves Labs).
18.5, and 19.5 for birth-dating) were injected i.p. with BrdU (50 mg/kg body
weight). Standard BrdU immunolabeling techniques were used after sodium
citrate steam treatment (antigen retrieval), and only heavily labeled cells were
templates. Digoxigenin-labeled riboprobes were made and used for ISH as de-
for brightfield imaging.
www.pnas.org?cgi?doi?10.1073?pnas.0905696106 Meechan et al.
Cell Counts. The 1-?m optical sections were collected on a Zeiss LSM-510 laser Download full-text
across at least two adjacent sections. In embryonic brains, cells were counted at
the level of mid-ganglionic eminences across the whole cortex from the cortical/
striatal boundary to the cortical hem. Also, counting boxes (200 ?m wide) were
bins were defined to assess distribution from the corticostriatal boundary to the
cortical hem. In postnatal cortex, cells were counted in coronal sections at the
level of the anterior commissure. Counting boxes (400 ?m wide) were placed at
dorsal, medial, and lateral sites.
number differences between LgDel and WT samples, and two-way ANOVA to
compare cell distributions. When differences were observed using ANOVA,
difference between specific bins.
ACKNOWLEDGMENTS. A.-S.L. was supported by National Institute of Child
M. Conte Grant MH64065. Confocal microscopy and ISH analysis used University
of North Carolina Neurosciences Center core facilities (NS031768).
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