1 Neuroanatomy and Interdisciplinary Center for Neurosciences (IZN), University
of Heidelberg, INF 307, D-69120 Heidelberg, Germany
2 European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg,
Germany
3 Department of Anatomy and Cell Biology, Hebrew University-Hadassah Medical
School, Jerusalem 91120-PO Box 12272, Israel
Author for correspondence (e-mail:
katrin.huber{at}ana.uni-heidelberg.de)
Accepted 22 August 2005
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SUMMARY |
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Key words: Sympathoadrenal cell lineage, Neuroendocrine cells, Chromaffin phenotype, SF1 (NR5A1), Mouse
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Introduction |
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Consequently, essential cues that trigger the chromaffin cell phenotype
have been assigned to the adrenal cortex. For decades, glucocorticoid hormones
from the adrenal cortex were assumed to influence crucially the decision of SA
progenitor cells to develop into chromaffin cells
(Unsicker et al., 1978;
Doupe et al., 1985
;
Anderson and Axel, 1986
;
Anderson and Michelsohn, 1989
;
Michelsohn and Anderson,
1992
). In-vitro studies with mammalian SA progenitors had
suggested that glucocorticoid signalling via the glucocorticoid receptor (GR)
governs two essential steps in chromaffin cell development: (1) the
suppression of neuronal traits; and (2) the induction of the
adrenaline-synthesizing enzyme phenylethanolamine-N-methyltransferase (PNMT)
in a majority of adrenal chromaffin cells
(Wurtman and Axelrod, 1966
;
Bohn et al., 1981
;
Anderson and Axel, 1986
;
Michelsohn and Anderson, 1992
;
Anderson, 1993
;
Unsicker, 1993
). However,
studies in mice deficient for the GR have failed to support the hypothesis of
an essential role of glucocorticoid signalling in chromaffin cell development:
GR/ mice have unaltered numbers of adrenal chromaffin
cells that are phenotypically normal in all respects, with the exception of
the lack of expression of PNMT and secretogranin II
(Finotto et al., 1999
).
Whether adrenal cortical cells might influence determination and
differentiation of chromaffin cells through mechanisms other than
glucocorticoid signalling has not been addressed.
The aim of the present study was therefore to determine whether the
specific phenotype of `adrenal' chromaffin cells can develop in the complete
absence of an adrenal cortical anlage. Mice with a targeted mutation in the
Sf1 gene (Nr5a1 Mouse Genome Informatics), which
codes for a nuclear orphan receptor, lack an adrenal cortex, testis and ovary
(Luo et al., 1994). Our study
provides evidence that chromaffin progenitors with largely normal marker
expressions and the typical ultrastructure of chromaffin cells develop in
Sf1 mutant mice in a location corresponding to the site where the
adrenal medulla is found in wild-type mice. A deficit in
migration/colonization, rather than reduced proliferation and cell death seem
to account for the 50% loss of chromaffin cells seen in
Sf1/ mice. Our results suggest that an
adrenal cortex is not essential for determining chromaffin cell fate, but may
be required for attracting and harbouring SA progenitors.
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Materials and methods |
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Histology
Pregnant mice were killed by CO2 asphyxiation. Embryos were
recovered, rinsed in cold PBS (pH 7.4) and fixed in PBS containing 4%
paraformaldehyde (PFA) overnight. Tissues were then rinsed three times with
PBS and placed in 15% sucrose in PBS for cryoprotection. Following overnight
immersion in sucrose, tissues were coated with OCT compound (Tissue Tek),
frozen on dry ice and stored at 70°C until further processing.
Tissues were then cut into 12 µm serial sections, mounted on Superfrost
slides, and air dried for 30 minutes, before performing in-situ hybridization
or immunfluorescence staining, respectively. For BrdU labelling of embryonic
adrenal glands pregnant females were injected i.v. with BrdU (Sigma, 0.4 ml of
an 8 mg/ml solution) at day 12.5 of gestation. Embryos were isolated 24 hours
after injection of BrdU and processed further as described above.
In-situ hybridization
Non-radioactive in-situ hybridization on cryosections and preparation of
digoxigenin-labelled probes for mouse neurofilament 68 (NF)
(Huber et al., 2002), mouse
tyrosine hydroxylase (TH) (Zhou et al.,
1995
), mouse RET (Pachnis et
al., 1993
), mouse PNMT (Cole et
al., 1995
) and mouse PHOX2B
(Pattyn et al., 1997
) were
carried out using a modification of the protocol of D. Henrique (IRFDBU,
Oxford, UK) as previously described
(Ernsberger et al., 1997
).
Mouse Sf1 (735-1336 bp) and mouse Scg10 (550-1178 bp) were
cloned by PCR using a pGEM-T vector system (Promega) following the
manufacturer's instructions. The plasmids were linearized with NotI
and transcribed with T7. If required, TH immunofluorescence staining was
carried out following in-situ hybridization as described below.
Immunofluorescence staining
For immunofluorescence staining, cryosections were pretreated with 10%
normal serum (corresponding to the secondary antibody) in PBS and 0.1% Triton
X-100, followed by overnight incubation at 4°C with polyclonal sheep
anti-TH (1:200, Chemicon International) or polyclonal guinea pig anti-SOX10
(1:1000, courtesy of Dr Michael Wegner, University of Erlangen). Sections were
then rinsed in PBS and incubated for 2 hours at room temperature with Cy3- or
Cy2-conjugated secondary antibody (Dianova) diluted 1:200 in 10% normal serum
in PBS and 0.1% Triton X-100. Sections were then rinsed in PBS, counterstained
with 4',6-Diamidino-2-phenylindole (DAPI) diluted 1:1000 in PBS, and
mounted with fluorescent mounting medium (Dako). For immunohistochemistry,
endogenous peroxidase was inhibited with 3% hydrogen peroxide in PBS for 15
minutes. Following incubation with 10% normal goat serum in PBS and 0.1%
Triton X-100, slides were then incubated at 4°C overnight with an
anti-rabbit vesicular monoamine transporter-1 antibody (VMAT1; 1:1000,
courtesy of Dr Eberhard Weihe, University of Marburg) in PBS containing 10%
normal goat serum and 0.1% Triton X-100. Sections were then washed with PBS
and incubated with a biotinylated goat anti-rabbit antibody (1:400, Vector
Laboratories) followed by avidin and biotinylated
horseradish-peroxidase-macromolecular complex (Vector Laboratories: Elite ABC
reagent) and DAB according to the manufacturer's instructions. For BrdU and
TH, double immunostaining cryosections were pretreated with DNAse (Roche, 1
mg/ml in 20 mmol/l Tris, 5 mmol/l MgCl2 and 1 mmol/l
CaCl2), rinsed three times in PBS, followed by overnight incubation
with polyclonal rat anti-BrdU antibody (Abcam) diluted 1:100 in 10% fetal calf
serum (FCS, Gibco) in PBS and 0.1% Triton X-100. After rinsing in PBS, tissues
were incubated with biotinylated rabbit anti-rat antibody (Vector
Laboratories) diluted 1:100 in 10% FCS in PBS and 0.1% Triton X-100 for 2
hours at room temperature. Sections were then rinsed with PBS and incubated
for 45 minutes with Cy2-conjugated streptavidin (Dianova) diluted 1:500 in
PBS. Subsequently, TH immunostaining was performed as described above.
TdT-mediated dUTP nick-end labelling analysis
For detection of apoptotic chromaffin cells, TdT-mediated dUTP nick-end
labelling (TUNEL) was performed on 12 µm cryosections using an ApoTag In
Situ APOPTOSIS Detection Kit (Oncor) according to the manufacturer's
instructions, as previously described
(Finotto et al., 1999).
Subsequently, TH-immunofluorescence staining was carried out as described
above.
Electron microscopy
For electron microscopy, E17.5 Sf1/
embryos and wild-type littermates were fixed in glutaraldehyde (1.5%) and
paraformaldehyde (1.5%) in phosphate buffer at pH 7.3 for 48 hours. The
embryos were subsequently cut into 500 µm thick slices using a Leica
VT1000E vibratome. Slices of the suprarenal region were postfixed overnight
and then processed for electron microscopy as previously described
(Finotto et al., 1999).
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Results |
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We next employed the markers TH, NF and SF1 to investigate whether cells with a presumptive adrenal chromaffin phenotype exist in mutant mice in a location corresponding to the adrenal medulla in wild-type mice. Fig. 1D and F show the spatial distribution of TH-ir and NF mRNA-positive cells in E13.5 SF1 deficient mice at the axial level, where the adrenal gland develops. Similar to the wild-type situation, TH-positive, NF-negative cells are located at the lateral surface of the suprarenal ganglion, but form a compact structure due to the lack of adrenal cortical cells. Thus, presumptive adrenal chromaffin progenitors migrate to and settle at the correct site for their further development even in the absence of an adrenal cortex. Moreover, presumptive adrenal chromaffin progenitors exhibit the correct NF-negative phenotype regardless of the absence of the adrenal cortex. Fig. 2 corroborates and extends these findings by showing that TH+/NF cells survive in their location associated with the suprarenal ganglion at E17.5 and 19.5 (the latter not shown). In addition, SCG10, another intermediate filament marker of sympathetic neurons, was employed and yielded identical results concerning differentiation of chromaffin progenitor cells (SCG10) and sympathetic neuron progenitors (SCG10+; Fig. 3A,B). Furthermore, Sf1/ chromaffin cells, like their wild-type counterparts, exhibited immunoreactivity for VMAT1 (Fig. 3C,D).
`Adrenal' chromaffin cells in Sf1/ mice exhibit all ultrastructural features of chromaffin cells
To further analyse the phenotype of `adrenal' chromaffin cells in
Sf1/ mice, we used serial semithin sections
and electron microscopy to reveal their precise topography and ultrastructure.
Fig. 4A demonstrates the
location of the right adrenal gland, the suprarenal ganglion, the upper pole
of the kidney, and the crus dextrum of the diaphragm in an E17.5 wild-type
embryo. Fig. 4C shows the
typical ultrastructure of adrenal chromaffin cells at this age. The cells
contain abundant chromaffin granules, i.e. large dense core vesicles (core
diameter >100 nm), which represent the ultrastructural hallmark of
chromaffin cells (Coupland,
1972; Coupland and Tomlinson,
1989
). The cells are tightly packed, associated with satellite
Schwann cells, and contacted by axon terminals (not shown). Adrenal cortical
cells (not shown) exhibit cholesterol droplets, smooth ER and tubular
mitochondria typical of steroid-producing cells
(Zwierzina, 1979
). The
dominating cell type in the suprarenal ganglion
(Fig. 4E) is a typical neuron
with a large nucleus, well-developed rough ER and Golgi areas, and few small
vesicles (core diameters <50 nm). In addition, there are Schwann cells,
axons and axon terminals (not shown).
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Chromaffin progenitor cells in Sf1 mutant mice lack PNMT and maintain RET expression
A subpopulation of adrenal chromaffin cells amounting to about 50% of the
total population at E19.5 synthesizes adrenaline and expresses the
synthesizing enzyme PNMT. Induction and maintenance of PNMT essentially
require glucocorticoids from the adrenal cortex
(Wurtman and Axelrod, 1966;
Finotto et al., 1999
). As
expected, Sf1/ mice lacking adrenal cortical
cells, by contrast to wild-type littermates, do not express PNMT mRNA in SA
cells located near the suprarenal ganglion
(Fig. 6C,G). RET is a receptor
tyrosine kinase, which serves as a receptor for GDNF family ligands
(Trupp et al., 1996
). It is
expressed by sympathetic neurons (Durbec
et al., 1996
) during distinct phases of their development. RET is
found on adrenal chromaffin cells at E13.5
(Allmendinger et al., 2003
) but
is subsequently downregulated, and becomes undetectable by E16.5.
Fig. 6D and H show that, unlike
the wild-type situation, RET expression persists in chromaffin cells of
Sf1/ mice. However, levels of RET expression
appear to be substantially lower in chromaffin cells than in the nearby
located sympathetic neurons of the suprarenal ganglion.
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To investigate whether the reduced number of TH+ chromaffin progenitor cells in Sf1 mutant mice was due to decreased proliferation, we investigated BrdU incorporation into chromaffin cells of wild-type and Sf1 mutant embryos. A single pulse of BrdU was administered to pregnant females at day 12.5 of gestation. Twenty-four hours later we determined the percentage of embryonic TH+ cells that had incorporated BrdU. As shown in Fig. 7B, there was no significant difference in the proportion of adrenal cells encountered in the synthetic phase of the cell cycle. Together, these data suggest that an early process, taking place by the time of cell migration and/or colonization of the adrenal anlage, that is different from proliferation or apoptosis, accounts for the smaller number of chromaffin cells present in the mutants.
Numbers of SOX10-, PHOX2B-, and TH-positive cells are reduced in the `adrenal' region of Sf1/ mice
At E12.5, NC-derived cells have started to colonize the adrenal anlage in
wild-type mice (Fig. 8B). Only
a few of these cells are immunoreactive for TH, while larger numbers express
PHOX2B (Fig. 8A), an early
marker for SA cells, or SOX10, a marker for undifferentiated NC cells
(Fig. 8A,B). Thus, at this age,
most `adrenal' chromaffin progenitors cannot be identified by combined TH and
NF labelling. Note that the TH-ir and the SOX10-ir populations do not overlap
in wild-type and Sf1/ mice. To clarify
whether chromaffin progenitor cells are numerically reduced in
Sf1/ mice as early as E12.5, we counted
numbers of PHOX2B+, TH+ and SOX10+ cells in
wild-type and Sf1/ mice in the para-aortic
region within a reproducibly defined space, describing as precisely as
possible the region where the adrenal anlage is located at this age. This
space was demarcated in the rostrocaudal position by the caudal extremity of
the lung bud and extended from there 500 µm caudally. The medial border of
this space was the midline of the dorsal aorta, the lateral border a vertical
plane 350 µm lateral to the midline. The dorsoventral limits were
horizontal planes through the dorsal wall of the aorta and a plane 200 µm
further ventrally (cf. Fig. 8B and
C). Fig. 8A shows
that in this region numbers of PHOX2B mRNA-positive cells, TH-ir and SOX10-ir
cells are reduced by about 25% in Sf1/ mice.
We therefore conclude that the `adrenal' region of
Sf1/ mice contains fewer chromaffin
precursors as early as E12.5 and that both early progenitors and cells that
are already TH-ir are affected.
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Discussion |
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SF1 is an orphan nuclear receptor, which closely resembles fushi tarazu
factor 1 isolated in Drosophila
(Lavorgna et al., 1991). It
has been implicated in the gene regulation of steroid hydroxylases and shown
by recombinant gene targeting to be absolutely required for the embryonic
development of the adrenal cortex and gonads
(Luo et al., 1994
). Initially,
it had been reported that Sf1/ mice
completely lack adrenal glands, i.e. adrenal cortex and medulla, although
Sf1 expression is restricted to the adrenal cortex. It was therefore
proposed that the NC-derived adrenal medullary chromaffin cells either fail to
migrate to the appropriate position or do not survive after migration due to
the lack of an adrenal cortical environment. More recently, it has been
reported that in Sf1/ embryos chromaffin
progenitors, identified by dopamine ß-hydroxylase (DBH)/LacZ, accumulate
at the correct rostrocaudal location at E13.5. However, according to this
study no tissue corresponding to the adrenal medulla could be detected at
E15.0 (Bland et al., 2004
).
Our analyses of Sf1/ mice provide
evidence that absence of an adrenal cortex does not substantially impair the
differentiation of chromaffin cells. About half the normal number of
chromaffin progenitors in Sf1 null mice are found in the location
where an adrenal medulla develops in wild-type mice, i.e. in close association
with the upper pole of the kidney and with a cluster of sympathetic neurons
that form the suprarenal ganglion. As in Sf1+/+ adrenal
glands, Sf1/ `adrenal' chromaffin cells
express TH, but, by contrast to sympathetic neuronal progenitors in the
suprarenal ganglion, virtually no NF68 mRNA. Analyses of E13.5
Sf1/ mice reveal that numbers of
TH+/NF cells in this location amount to about 50%
of adrenal medullary chromaffin progenitor cells in Sf1+/+
animals. Numbers of TH+/NF cells increase in both
Sf1/ and Sf1+/+ mice by
a factor of about 3.5 until E17.5. Together with the evidence from BrdU
incorporation, these data suggest that physiologically occurring proliferation
of chromaffin progenitors at this age is not impaired (cf.
Finotto et al., 1999;
Huber et al., 2002
). The
frequent detection of mitotic figures in electron microscopic samples and the
absence of TUNEL-positive chromaffin progenitors in both genotypes further
support this notion. Chromaffin progenitor cells in Sf1 mutant mice
display all ultrastructural hallmarks of this cell type, are positive for
VMAT1 and are contacted by preganglionic axon terminals, suggesting that
preganglionic innervation is not grossly impaired. As expected, the absence of
an adrenal cortex in Sf1/ mice abrogates
expression of PNMT, which in mammals essentially requires high levels of
glucocorticoids (Pohorecky and Wurtman,
1968
; Wurtman and Axelrod,
1966
). The only other alteration that we found in the
Sf1/ chromaffin cell phenotype concerns
persistent expression of RET until E19.5, which in the wild-type situation is
extinguished at E15.5 (Allmendinger et al.,
2003
). The significance of this difference remains to be
investigated.
Our analysis of chromaffin cell development in Sf1 mutant mice
provides conclusive evidence that the adrenal cortex is not an absolute
prerequisite for the determination and differentiation of the chromaffin
phenotype. The close association of well-differentiated chromaffin tissue and
neurons in the suprarenal ganglion further argues against a crucial role of
local environmental factors in the diversification of SA derivatives. This
adds to an increasing body of evidence suggesting that a segregation of the
two phenotypically distinct cell types, neurons and chromaffin cells, has
probably occurred prior to them reaching their final destination. In support
of this notion, recent studies in chick embryos have revealed an early
heterogeneity of SA progenitors concerning expression of neurofilament
(Ernsberger et al., 2005).
Furthermore, the existence of chromaffin tissue outside the adrenal gland
(extra-adrenal chromaffin cells) similarly suggests that specification of
chromaffin cells is unlikely to depend crucially on the adrenal cortex.
Extra-adrenal chromaffin cells are abundant in mammals at birth (cf.
Coupland, 1965
), but
subsequently undergo massive cell death for reasons that are still unknown.
Finally, comparative histology of chromaffin tissue in lower vertebrates from
elasmobranchs to teleosts also suggests that the chromaffin phenotype can
develop independently from adrenocortical (inter-renal) tissue
(Chester and Philipps, 1986
;
Matty, 1985
)
Generally, the segregation of subpopulations of progenitors from the
multipotent NC population may take place before, during or after migration
(Le Douarin and Kalcheim,
1999). As the adrenal cortex apparently does not specify the
chromaffin cell phenotype, a postmigratory specification of the SA progeny
into neurons and chromaffin cells seems unlikely. Therefore, signals for
chromaffin cell specification probably need to be sought prior to the arrival
of the progenitor cells at the adrenal target. Given the wide distribution of
chromaffin cells over all cervical, thoracic and lumbar levels, and their
presence in virtually all sympathetic ganglia, paraganglia, adrenal gland and
in lumbar extra-adrenal chromaffin tissue, we consider it to be unlikely that
distinct segmental signals, as for example provided by the Hox code
(Creuzet et al., 2002
),
contribute to the specification of the chromaffin cell phenotype. However, we
have noted in the context of previous studies that the adrenal anlage of mouse
embryos is colonized at E11.5 by NC cells that express MASH1 and PHOX2B, but
are still TH-negative, while nearby located sympathetic neurons already
express TH. This finding might be explained by different kinetics of TH
induction in sympathetic and chromaffin progenitors. Alternatively, it may
suggest that chromaffin cells and sympathetic neurons are not derived from a
common TH+ SA progenitor, but develop independently from NC cells,
following different maturation schedules. Thus, chromaffin progenitors may
represent a late migrating wave of NC derivatives. A time-dependent
topographical segregation and fate-dependency of NC progenitors has previously
been suggested by studies analysing the fate restrictions of late versus early
migrating cephalic and trunk NC derivatives
(Raible and Eisen, 1996
). NC
cells colonizing the adrenal anlage may not even require BMP-4 derived from
the dorsal aorta but may receive this important signal from BMP-4 expressing
peri-adrenal cells (K.H., unpublished).
Although the present study rules out an essential fate-determining role of the adrenal cortex for chromaffin progenitor cells, the missing 50% fraction of chromaffin cells in Sf1/ embryos may suggest a role for the adrenal cortex in attracting and harbouring chromaffin cells. Our analysis of the `adrenal' region in E12.5 Sf1/ mice indicates that numbers of SOX10+ NC progenitors as well as PHOX2B- and TH-positive SA cells are reduced by 25%. The relatively modest cell loss, compared with the 50% loss of chromaffin progenitor cells at E13.5, is probably due to counting a wider range of progenitor cells, possibly including non-chromaffin progenitors, within a larger volume. Alternatively, since the cells have just started to invade the adrenal cortical anlage at E12.5, these results may indicate that fewer cells settle in their final location between E12.5 and 13.5. In light of the uniform 25% loss of SOX10-, PHOX2B- and TH-positive cells, an impairment of differentiation of SOX10-positive NC cells into PHOX2B- and TH-positive chromaffin progenitors seems unlikely. The Sf1/ phenotype can be interpreted in several ways, including deficits in migration of NC progenitor cells to the adrenal region. We would favour, however, a hypothesis that takes into account the capacity of the adrenal anlage to provide space and an environment permissive for harbouring cells.
In conclusion, the present study suggests that the adrenal cortex is not essentially required for chromaffin phenotype specification. However, it is necessary for assembling the complete set of chromaffin cells in the correct location.
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ACKNOWLEDGMENTS |
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Footnotes |
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