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First published online August 18, 2003
doi: 10.1242/10.1242/dev.00666
RESEARCH ARTICLES: DEVELOPMENT AND DISEASE |
1 Department of Cell Biology, Japanese Foundation for Cancer Research (JFCR)
Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-Ku, Tokyo 170-8455,
Japan
2 Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku
University School of Medicine, Sendai 980-8574, Japan
3 Miyagi Insurance Hospital, Sendai 981-1103, Japan
4 Laboratory for Cell Culture Development, Brain Science Institute, RIKEN, Wako,
Saitama 351-0198, Japan
5 Mouse Functional Genomics Research Group, RIKEN Genomic Sciences Center,
Kanagawa 244-0804, Japan
6 Division of Molecular Genetics, Center for Translational and Advanced Animal
Researches on Human Diseases, Tohoku University School of Medicine, Sendai
980-8575, Japan
* Author for correspondence (e-mail: tnoda{at}ims.u-tokyo.ac.jp)
Accepted 12 June 2003
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SUMMARY |
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TOP
SUMMARY
Introduction
Materials and methods
Results
Discussion
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Key words: Brn1, Henle's loop, Kidney, Distal tubule formation, POU transcription factor
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Introduction |
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SUMMARY
Introduction
Materials and methods
Results
Discussion
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;
Schedl and Hastie, 2000). The
mammalian kidney contains many nephrons, each consisting of a glomerulus and
tubules. The glomerulus acts to filter the plasma and the tubules, which are
divided into proximal, intermediate and distal, function to reabsorb water and
small molecules such as ions from the filtrate
(Bachmann and Kriz, 1998).
Among the nephron tubules, Henle's loop (HL) has a unique structure and is
essential for hypertonic urine production, which conserves water and ions to
maintain homeostasis in the body (Greger,
1985). Although a number of molecules including transcription
factors and growth factors have been implicated by genetic screens in the
early phases of mammalian kidney development, the mechanisms controlling the
unique and complex nephron patterning remain to be elucidated
(Kuure et al., 2000;
Schedl and Hastie, 2000). This
patterning is a key process for the establishment of kidney function later in
development.
Transcription factors are essential for the development of complex organ
systems. POU transcription factors, which carry a common DNA binding motif
called a POU domain, regulate a variety of developmental processes. Brn1
(Pou3f3 - Mouse Genome Informatics) and Brn2 (Pou3f2 - Mouse Genome
Informatics) are members of the class III family of mammalian POU
transcription factors, and share extremely high sequence homology within the
POU domain. They are both prominently expressed in the central nervous system
during embryonic development (He et al.,
1989). These two factors show a high level of redundancy, as
targeted mutagenesis of either of these genes only leads to changes in very
restricted regions of the brain. Brn1-deficient mice die within 48 hours of
birth, but show histological abnormalities only in the hippocampus region
(data not shown), which are not sufficient to explain their postnatal death.
Analysis of the Brn1/Brn2 double mutants showed that Brn1
and Brn2 regulate the production and positioning of neocortical neurons
(McEvilly et al., 2002;
Sugitani et al., 2002), but
the cause of death in the Brn1- deficient mice remains unclear.
Brn1, but not Brn2 or any other class III POU proteins, is also expressed
in the developing kidney of rat embryos, but its function here remains unknown
(He et al., 1989). We describe,
in detail, our analysis of the spatial and temporal patterns of Brn1
expression in the developing mammalian kidney. Histological and functional
changes to the kidney in Brn1- mutant mice were also analyzed. The results
clearly suggest that Brn1 may play an essential role not only in the formation
of the HL, distal convoluted tubule (DCT) and macula densa (MD) structure in
the developing kidney, but also in the function of the thick ascending limb
(TAL) of HL in the adult kidney.
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Materials and methods |
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SUMMARY
Introduction
Materials and methods
Results
Discussion
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). Of 700
G418-resistant colonies, we identified eleven properly targeted clones as
determined by Southern blot analysis. Two independent ES cell clones were
microinjected into C57BL/6J blastocysts, resulting in the birth of male
chimeras. Germline transmission of the disrupted Brn1 allele was
achieved by mating with C57BL/6J females.
Antibodies
A polyclonal anti-Brn1 antibody was generated by immunizing a rabbit with
the synthetic polypeptide, PDDVYSQVGIVSAD, corresponding to amino acids
469-482 of mouse Brn1. The specificity of the Brn1 antibody was confirmed by
western blot analysis (Fig.
1B), which was performed as previously described
(Yao et al., 2002).
|
).
Histology, immunohistochemistry and electron microscopy
For light microscopy, organs were fixed in Bouin's fixative, embedded in
paraffin wax and sectioned. Kidney morphology was visualized using 6 µm
longitudinal or coronal sections stained with either Hematoxylin and Eosin or
periodic acid-Schiffs (PAS). For Brn1 immunohistochemistry, organ samples were
fixed in 4% paraformaldehyde (PFA) overnight. Cryostat sections of 10 µm
thickness were cut then incubated with anti-Brn1 antibody overnight. Signals
were visualized using a Vectastain ABC kit (Vector Laboratories),
counterstained with kernechtrot, dehydrated and mounted on glass slides. For
Caspase 3, phosphorylated MAPK (ERK1/2), and Bcl2 immunohistochemistry, organ
samples were fixed in 4% paraformaldehyde (PFA) overnight. Paraffin wax
embedded sections were cut (6 µm) then incubated with anti-cleaved
caspase-3 antibody (Asp175) (Cell Signaling Technology) or anti-
phosphorylated MAPK (ERK1/2) antibody (Cell Signaling Technology) or
anti-Bcl-2 antibody (BD PharMingen) overnight. Signals were visualized using a
Vectastain ABC kit (Vector Laboratories), counterstained with Hematoxylin,
dehydrated, and mounted on glass slides. For electron microscopy, tissues were
fixed in 2% PFA/1% glutaraldehyde in 0.1 M phosphate buffer and embedded in
Epon 812 resin. Semi-thin sections (1 µm) were used for Toluidine Blue
staining, while ultrathin sections were prepared for examination in a
transmission electron microscope.
Cell proliferation assay
E16.5 timed-pregnant heterozygous females were injected intraperitoneally
with BrdU (Amersham) at 100 mg kg-1 of body weight. Approximately 3
hours after injection, females were sacrificed and the embryos recovered.
Kidneys dissected from the embryos were fixed in Bouin's fixative, embedded in
paraffin wax and sectioned longitudinally at a (6 µm). Sections were then
incubated with anti- BrdU antibody (Becton Dickinson) diluted 1:100 overnight
at 4°C. Signals were visualized using a Vectastain ABC kit. Following
counterstaining with Hematoxylin, samples were dehydrated and mounted. Three
animals for each genotype were subjected to analysis. Total and stained cells
were counted in at least four independent Henle's loops to give a percentage
of BrdU-positive cells. The average percentage for each animal was then
subjected to statistical analysis.
TUNEL assay
Kidneys were dissected from newborn mice, fixed in 10% neutral formalin and
embedded in paraffin wax. Sections were cut at 6 µm and subjected to a
TUNEL assay. The labeling of fragmented nuclear DNA with terminal
deoxynucleotide transferase (Tdt) was performed using an ApopTag Peroxidase
Kit (Interogen).
In situ hybridization (ISH)
Organs were fixed in 4% PFA overnight. In situ hybridization of 10 µm
cryostat sections was performed as described
(Minowa et al., 1999).
Riboprobes were synthesized using the following mouse cDNAs: Ptger3
(10-364), Umod (625-932), Nkcc2 (Slc12a1 - Mouse Genome
Informatics) (3086-3331), Ncc (360-741), Ncx1 (Slc8a1 -
Mouse Genome Informatics) (442-808), ßENaC (Scnn1b - Mouse
Genome Informatics) (658-976) and Nos1 (167-516).
RNase protection assay (RPA)
mRNA levels were measured using an RPA as previously described
(Nakai et al., 1995).
32P-labeled riboprobes were generated from the cDNAs described
above for use in in situ hybridization. The mouse cDNAs of Bsnd
(203-688), Egf (1084-1546), Clcnk1l (844-1322), and
Kcnj1 (124-511) were also used for RPA. A plasmid containing 
100
bp of the mouse Gapd cDNA was a kind gift from Dr A. Orimo (Saitama
Medical School, Iruma, Saitama). The intensities of the radioactive protected
bands were quantified on an Image Analyzer (Fuji Film). Test signals were
normalized to the Gapd signal for each sample. The ratios of observed
to wild-type signal were then calculated.
Clinical chemistry
For newborn mice, blood samples were collected by decapitation, while urine
samples were collected by forced voiding. In adult mice, blood was collected
retro-orbitally using capillary tubes. Urine samples were collected by
spontaneous voiding. Serum urea nitrogen levels were measured using a UN-B
Test Wako (Wako). Serum creatinine and electrolyte concentrations were
measured using DriChem (Fuji Film). Serum and urine sample osmolalities were
measured using a Fiske Osmometer Model 110 (Fiske Associates). To determine
the daily urine output, mice were kept in metabolic cages under euhydrated
conditions.
Glomerular maturity index and glomerular counts
Six newborn animals for each genotype were analyzed. The glomerular
maturity index was calculated as described previously
(Niimura et al., 1995). The
maturity index determined for each animal was an average of the score for all
glomeruli present in a median longitudinal section. The total number of
glomeruli was also quantitated in a median longitudinal section for each
animal.
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Results |
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SUMMARY
Introduction
Materials and methods
Results
Discussion
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20%
less in weight than those of either Brn1+/+ or
Brn1+/- mice (Table
1), suggesting a hypoplasticity of the Brn1-/-
kidneys. Histological analyses showed equivalent numbers of collecting ducts
(CDs) in the medulla region of both Brn1+/+ and
Brn1-/- kidneys (Fig.
1D,E, data not shown). PAS staining, however, revealed drastically
reduced numbers of HLs in the kidneys of Brn1-/- mice
(Fig. 1D,E). In addition, the
areas occupied by interstitial cells between the CDs were more prominent in
Brn1-/- kidneys, consistent with the HLs being replaced by
these cells (Fig. 1D,E). By
contrast, no remarkable changes were observed in the cortices of
Brn1-/- kidneys (Fig.
1F,G). The number of glomeruli and the extent of their maturation
in the kidneys of Brn1-/- mice were not significantly
different from those of Brn1+/+ or
Brn1+/- mice (Table
1). In addition, there was no significant difference in proximal
tubule number between the Brn1 mutant mice (data not shown), although
these numbers were difficult to quantitate.
To determine the function of Brn1 in kidney development, we analyzed its
expression during mouse development. Throughout the initial phases of kidney
development, we could not identify any Brn1-immunoreactive cells in any part
of the embryonic kidney. Brn1 expression was first identified in a spherical
cyst (Fig. 2A,B), a region of
the renal vesicle containing early epithelial cells transformed from the
metanephric blastema. This cyst, through a series of invaginations and
elongations, initiates nephrogenesis to generate first comma-shaped and then
S-shaped bodies (Kuure et al.,
2000; Schedl and Hastie,
2000). Brn1 was specifically detected in the prospective HL, DCT
and the MD within S- shaped bodies (Fig.
2C,D). During a subsequent stage in the development of these
bodies into mature nephrons, Brn1 was detected within the developing HL, DCT
and MD, but not in the glomerulus, proximal tubule or CD
(Fig. 2E,F). In mature
nephrons, Brn1 expression endured in the MD and DCT, but became regionalized
to the TAL in HL (Fig. 2G-I).
This expression pattern persisted through adulthood.
|
). Thus, newer
nephrons are sequentially added to the nephrogenic zone, the outer region of
the cortex beneath the renal capsule, while older nephrons move into deeper
regions of the cortex with elongating HLs extending toward the medulla. Three
distinct stages of developing HL were observed in the wild-type mouse kidney
at E16.5, similar to the same stages in rat
(Neiss, 1982). The first
stage, the anlage, is a U-shaped structure located in the nephrogenic zone
(Fig. 3A,D). The next stage,
the primitive loop, elongates through the boundary of the cortex and medulla,
with a bend lying within the medullary ray or outer medulla
(Fig. 3B,D). In both stages,
HLs contain cuboidal epithelial cells undergoing multiple mitoses. HLs in
these stages were also observed within the Brn1-/- kidney
at E16.5. In wild-type mice, we detected immature loops, the third stage of
the developing HL. These loops possess a dilated tubule lumen and a
morphologically differentiated tubule epithelium
(Fig. 3C,D). Some bends in
these immature loops reach almost to the papillary tip, the innermost region
of the kidney. Cytologically, the descending limb of the immature loop
displays a darkly stained thin epithelium. By contrast, the ascending limb of
the immature loop contains lightly stained, tall cuboidal epithelial cells
(Fig. 3C), defining the
differentiation and proliferation of tubular epithelial cells that
characterizes the immature loop differentiation stage. We could not detect any
immature loops within the Brn1-/- kidney, despite an
extensive analysis. To confirm this observation, we quantitated the developing
HLs in Brn1 mutant kidneys at E16.5
(Fig. 3E,F). This analysis
confirmed the absence of immature loops in Brn1-/- kidneys
(Fig. 3F). The number of
primitive loops in Brn1-/- kidneys was twice that found in
either Brn1+/+ or Brn1+/- kidneys
(Fig. 3E). This proportion
remained true for mice at E17.5 or P0 (data not shown). We concluded that HL
development was either perturbed or severely retarded at the primitive loop
stage in Brn1-deficient kidneys.
|
). In
Brn1-/- kidneys lacking immature loops
(Fig. 3P), significant numbers
of apoptotic cells were detected throughout the primitive loop bend
(Fig. 3N, arrows). Apoptotic
cells were never detected in this region of either Brn1+/+
or Brn1+/- kidneys
(Fig. 3M). To determine whether
apoptosis observed in Brn1+/+ immature loop and
Brn1-/- primitive loop is associated with the activation
of caspase cascade, we examined active caspase 3 expression by
immunohistochemical analysis. Active caspase 3-positive cells were detected in
almost the same manner to that observed by TUNEL assay described above
(Fig. 3Q-T). This result
suggests that apoptosis in both Brn1+/+ immature loop and
Brn1-/- primitive loop was induced through the activation
of caspase cascade. We further examined the expressions of phosphorylated MAPK
(ERK1/2) and anti-apoptotic protein Bcl2, both of which are known to suppress
apoptosis. Their expressions were not detected in HLs throughout their
developmental stages by immunohistochemical analysis. Therefore, we could not
find any specific changes in their expressions for Brn1+/+
immature loop and Brn1-/- primitive loop (data not shown).
These results exclude the possible involvement of MAPK (ERK1/2) and Bcl2 in
the apoptosis induction in Brn1-/- primitive loops or in
the apoptosis suppression in Brn1+/+ primitive loops.
Taken together, Brn1 possibly suppresses apoptosis in primitive loop and,
therefore, Brn1 deficiency may result in the premature induction of
physiological apoptosis in primitive loop. Primitive loop apoptosis may at
least in part contribute to the perturbation of HL development in
Brn1-/- mice. These results support an essential role for
Brn1 in the growth and survival of developing tubular epithelial cells.
Differentiation of HLs, MD and DCT is suppressed in
Brn1-/- kidney
Although tubular epithelial cells within the wild-type primitive loop
retain an immature appearance histologically, several molecular markers for HL
are identifiable in the primitive loop, suggesting the initiation of
differentiation. Umod, a gene that encodes a glycoprotein marker of
the TAL (Bachmann et al.,
1990), is first expressed in the anlage. Ptger3, a
receptor for prostaglandin E2
(Breyer et al., 1993), and
Nkcc2 (Slc12a1), a bumetanide-sensitive Na-K-2Cl
co-transporter (Schmitt et al.,
1999), begin to be expressed in the prospective TAL region of the
primitive loop. In situ hybridization analysis of P0 kidney, however, failed
to detect mRNA expression for any of these genes in the HL primitive loop in
Brn1-/- mice (Fig.
4A). This observation was confirmed using RNase protection assays
(RPA) of mRNA extracted from P0 Brn1-/- kidneys (see
Fig. 6). These results suggest
that differentiation of the HL primitive loop is perturbed in
Brn1-/- mice. This differentiation defect may be
independent from the defect in HL elongation described above. As Umod
expression should be initiated in the anlage stage prior to the observation of
any growth defects or induced apoptosis in Brn1-/- kidney,
the lack of Umod expression suggests that the Brn1
deficiency results in a far more complex developmental defect arising at the
earlier stages of differentiation.
|
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;
Skott and Briggs, 1987), while
the DCT facilitates the reabsorption of NaCl and Ca2+
(Bachmann and Kriz, 1998). We
also examined the MD and DCT in Brn1 mutant kidneys at P0,
histologically and by in situ hybridization. In Brn1+/+
and Brn1+/- kidneys, the MD, consisting of a plaque of
columnar tubular cells protruding into the lumen within the cortical TAL of
HL, was found adjacent to the hilus of the glomerulus
(Fig. 4B). In
Brn1-/- kidneys, however, the same cells did not exhibit
any of the characteristic features of the MD. Instead, these cells displayed
the same morphology as the surrounding cells
(Fig. 4B). In situ
hybridization of Brn1-/- nephrons, including the putative
MD region, failed to detect expression of the constitutive type 1 isoform of
the nitric oxide synthase gene (Nos1) or Ptger3
(Fig. 4B), characteristic
markers of MD cells (Breyer et al.,
1993; Fischer et al.,
1995). By immunohistochemical analysis, phosphorylated MAPK
(ERK-1/2) was detected in macula densa and the surrounding cells in
Brn1+/+ kidney, but not in Brn1-/-
kidney (data not shown). Electron microscopic analysis also failed to identify
cells with any of the typical feature of MD cells, such as luminal microvilli
or basal and lateral membrane foldings
(Bachmann and Kriz, 1998;
Fischer et al., 1995;
Schmitt et al., 1999)
(Fig. 5). These results suggest
that the Brn1 deficiency also disrupted development of the MD. Interestingly,
the morphology of the putative TAL, including the putative MD, in
Brn1-/- kidneys differed from that of
Brn1+/+ and Brn1+/- TAL. The putative
TAL of Brn1-/- kidneys retained the undifferentiated
features of tubular cells, including simple cell membranes and small, sparse
mitochondria with the cytoplasm (Fig.
5), supporting the observation that the differentiation of TAL
cells is perturbed in Brn1-/- kidneys.
|
). We
detected Ncc expression by in situ hybridization in both
Brn1+/+ and Brn1+/- kidneys, but not
in Brn1-/- kidneys
(Fig. 4C). The Na/Ca exchanger
gene, Ncx1/Slc8a1 is normally expressed in the distal region
of the DCT and the connecting tubule (CNT)
(Schmitt et al., 1999), a
region of tubule that follows the DCT. In Brn1-/- kidneys,
Ncx1/Slc8a1 expression differed from that observed in
Brn1+/+ or Brn1+/- kidneys
(Fig. 4C). The development of
CNT appeared normal in Brn1-/- kidneys, as judged by the
expression pattern of the amirolide- sensitive epithelial Na+
channel gene, ßEnaC/Scnn1b, which is a marker for CNT
and CD (Schmitt et al., 1999).
The pattern was indistinguishable from that of Brn1+/+ or
Brn1+/- kidneys (Fig.
4C). These results show that the expression of several molecules
essential for DCT function was reduced in the Brn1-/-
kidney. Electron microscopic analysis also demonstrated that there were some
immature cells in the DCT region of Brn1-/- kidneys, which
were not present in either Brn1+/+ or
Brn1+/- kidneys (data not shown). Together, these data
suggest that the differentiation of DCT cells is perturbed by a deficiency in
Brn1.
Expression levels of Umod, Ptger3, Nkcc2,
Kcnj1 and Bsnd were significantly reduced in the TAL of HLs
of Brn1+/- kidneys
In mature nephrons, Brn1 expression in the HLs was regionalized within the
TAL region (Fig. 2H,I). RPA
analysis of mRNA extracted from Brn1-/- kidneys at P0
indicated a drastic reduction in the expression of several genes that are
normally expressed in the TAL (Fig.
6), confirming the differentiation defect of HL. Interestingly,
this analysis also demonstrated significant reductions in the expression
levels of Umod, Ptger3, Nkcc2, Kcnj1 (encoding an apical
K+ channel) (Simon and Lifton,
1998) and Bsnd (encoding a basolateral Cl-
channel ß-subunit) (Birkenhager et
al., 2001; Estevez et al.,
2001) in Brn1+/- kidneys at P0
(Fig. 6). Morphologically,
these kidneys were unaltered. We also identified significant reductions in the
expression of these genes in Brn1+/- adult kidneys
(Fig. 6), in which Brn1
expression within the TAL is half of that in wild-type kidneys (data not
shown). Nkcc2, Kcnj1 and Bsnd are essential for the
reabsorption of NaCl by TAL cells
(Birkenhager et al., 2001;
Estevez et al., 2001;
Simon and Lifton, 1998;
Takahashi et al., 2000), which
is a necessary step in hypertonic urine generation as it establishes a
countercurrent multiplier system (Greger,
1985). We therefore wanted to examine kidney function in the adult
Brn1+/- mice. Blood data (BUN, creatinine, Na+,
K+, Cl- and osmolality) and urine data (osmolality and
daily urine volume) in Brn1+/- mice under euhydrated
conditions were indistinguishable from that of wild-type mice (data not
shown). In addition, neither urine osmolality 2 hours after intraperitoneal
injection of dDAVP (1-desamino-8-D-argininevasopressin; 0.4 µg
kg-1) nor percent body weight loss after 24 hours water deprivation
revealed any significant difference in the two genotypes (data not shown).
Therefore, it was clear that adult Brn1+/- mice retain
sufficient kidney function to generate hypertonic urine that is
indistinguishable from that of wild-type mice. These results suggest that TAL
cells in the Brn1+/- kidney are functionally normal and
the significant reduction in gene expression may not result from a general
dysfunction of TAL cells. Therefore, the Brn1 gene dosage effects on the
expression levels of functionally essential TAL genes imply that Brn1 is
essential for TAL function by activating the expression of these genes.
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Discussion |
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SUMMARY
Introduction
Materials and methods
Results
Discussion
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The HL of a nephron is a unique structure that enables the generation of
hypertonic urine, a function unique to birds and mammals
(Casotti et al., 2000). Brn1,
however, is also expressed in fish (zebrafish), suggesting that Brn1 pre-dates
the establishment of HLs phylogenetically. Brn1 might have functioned
originally in the development of DCT in fish, then the gene may have acquired
an additional function to support HL development in birds and mammals. We
recently showed that Brn1 functions in the development of neocortical neurons
in mice (Sugitani et al.,
2002). Because of the functional complementation between Brn1 and
Brn2 during neocortical development, Brn1-/- mutant mice
may exhibit a severe phenotype only within the kidneys, where Brn1 is the only
class III POU factor expressed during development
(He et al., 1989). The mode of
Brn1 function in developing neocortical neurons is similar to its function in
HL development, as Brn1 functions in both the proliferation and
differentiation of precursors in both situations. In addition, Brn1 commonly
plays an essential role in later phases of the developmental process
(McEvilly et al., 2002;
Sugitani et al., 2002).
Nephrons require Brn1 function mainly during late development. The molecular
pathways activated downstream of Brn1, however, are quite different between
these two systems. In contrast to the activation of TAL-specific genes in
developing HLs, Brn1 activates Dab1-dependent positioning processes in
neocortical neurons (Sugitani et al.,
2002). Therefore, the involvement of an additional molecule(s)
specifying the pathways downstream of Brn1 is likely. Identification of such
factors would aid our understanding of the molecular mechanisms underlying HL
development.
We also elucidated an essential role of Brn1 in the nephron function in
this study. The involvement of Brn1 in the regulation of gene expression in
TAL of HLs was clearly shown by the significant reductions in the expression
levels of Umod, Ptger3, Nkcc2, Kcnj1 and Bsnd in
Brn1+/- kidneys. As neither histological abnormality nor
nephron dysfunction was observed in Brn1+/- kidneys as
described above, expression levels of these genes in
Brn1+/- kidneys seemed to be sufficient to support the
development and function of HLs. Among these genes, Nkcc2, Kcnj1 and
Bsnd are essential for the reabsorption of NaCl by TAL cells
(Birkenhager et al., 2001;
Estevez et al., 2001;
Simon and Lifton, 1998;
Takahashi et al., 2000), which
is a necessary step in hypertonic urine generation as it establishes a
countercurrent multiplier system (Greger,
1985). Furthermore, their mutations have been shown to cause
'Bartter's syndrome', which describes a set of autosomal recessively inherited
renal tubular disorders characterized by polyuria with hypokalemia and
metabolic alkalosis (Birkenhager et al.,
2001; Estevez et al.,
2001; Simon and Lifton,
1998; Takahashi et al.,
2000). Therefore, the involvement of Brn1 mutations in
these individuals should also be analyzed in the next study.
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ACKNOWLEDGMENTS |
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SUMMARY
Introduction
Materials and methods
Results
Discussion
REFERENCES |
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