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Volume 17, Number 11,
Issue of June 1, 1997
pp. 4275-4281
Copyright ©1997 Society for Neuroscience
Norepinephrine Facilitates the Development of the Murine Sweat
Response But Is Not Essential
A. Tsahai Tafari,
Steven A. Thomas, and
Richard D. Palmiter
Howard Hughes Medical Institute, Department of Biochemistry,
University of Washington, Seattle, Washington 98195-7370
ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
During development, the sympathetic neurons innervating sweat
glands undergo a neurotransmitter switch from noradrenergic to
cholinergic between postnatal day (P) 4, when the sympathetic neurons
first contact the sweat glands, and P21. Several in
vitro experiments suggest that norepinephrine (NE), produced by
sympathetic neurons, stimulates sweat glands to produce a factor that
then induces the phenotypic switch. We tested this hypothesis in
vivo using dopamine 
-hydroxylase-deficient mice (DBH 
/),
which are unable to synthesize NE and epinephrine, and tyrosine
hydroxylase-deficient mice (TH /), which are unable to synthesize
any catecholamines. The cholinergic agonist pilocarpine and
electrostimulation of the sciatic nerve both elicited a sweat response
in adult DBH / mice that was indistinguishable from the response of
controls, and the cholinergic antagonist atropine effectively blocked
these responses. We did note, however, a 1- to 2-week delay in the
acquisition of the sweat response in DBH / mice. Although
diminished in magnitude, a sweat response to pilocarpine was also noted
in TH / mice at P21. Immunohistochemistry demonstrated that TH and vasoactive intestinal peptide were detectable at P14 and increased to
adult levels by P21 in DBH +/ and DBH / mice. These observations indicate that NE is not essential for the acquisition of the
cholinergic phenotype, but it may facilitate its postnatal
development.
Key words:
norepinephrine;
acetylcholine;
sweat gland factor;
mouse;
sweating;
dopamine -hydroxylase;
tyrosine hydroxylase;
vasoactive
intestinal peptide
INTRODUCTION
Rodent sweat glands are coiled tubules found
primarily on the digits and footpads of the paws (Kennedy et al.,
1984
). They mature during the second and third postnatal weeks and are
thought to provide enhanced tactile sensitivity rather than
thermoregulation (Wechsler and Fisher, 1968). Although the glands
develop a normal morphology without innervation (Yodlowski et al.,
1984), a sweat response depends on innervation by the sympathetic
nervous system (Stevens and Landis, 1988). The sympathetic neurons that
initially make contact with the developing sweat glands at P4 are
noradrenergic: they express tyrosine hydroxylase (TH) and dopamine
-hydroxylase (DBH) and produce norepinephrine (NE) (Landis and
Keefe, 1983). Beginning at about postnatal day (P) 11 and continuing to
P21, however, there is a gradual loss of these noradrenergic markers and the acquisition of the cholinergic markers choline
acetyltransferase and acetylcholinesterase, as well as the
neuropeptides, vasoactive intestinal peptide (VIP), and calcitonin
gene-related peptide (Landis and Keefe, 1983; Leblanc and Landis, 1986;
Stevens and Landis, 1987; Landis et al., 1988). Sweating in the adult
(P21 and older) is elicited by cholinergic agonists and blocked by cholinergic antagonists. Noradrenergic agonists do not elicit sweating
nor do noradrenergic antagonists block sweating (Stevens and Landis,
1987).
The switch from noradrenergic to cholinergic phenotype depends on the
interaction of the neurons with the target tissue. Schotzinger and
Landis (1988) showed that when a rat footpad was transplanted to the
flank of a neonatal rat, the sympathetic neurons that would normally
remain noradrenergic become cholinergic after contact with the
transplanted footpads. The converse experiment showed that when a
normal noradrenergic target was transplanted to the foot, the neurons
maintained their noradrenergic phenotype (Schotzinger and Landis,
1990). In vitro experiments indicated that a soluble factor
called sweat gland cholinergic differentiation factor (SGF) is released
from footpads to induce switching of the neuronal phenotype (Habecker
and Landis, 1994). The production of SGF by the footpads is thought to
depend on innervation (Habecker et al., 1995). A logical candidate for
the factor derived from the noradrenergic neurons is NE. Consistent
with this idea, Habecker and Landis (1994) showed that noradrenergic
antagonists for either 
1- or -receptors blocked
neuronal induction of SGF in neuron/footpad co-cultures and that
forskolin, a direct activator of adenylyl cyclase, stimulated the
production of SGF in footpads cultured without neurons.
Innervation is also necessary for cholinergic agonists to elicit a
sweat response (Grant et al., 1991). Cholinergic receptors, of the
muscarinic subtype m3, appear in normal abundance and have normal affinity for cholinergic agonists, but in the absence of innervation they cannot elicit a sweat response. Thus, some stimulus from the nerves is also responsible for activation of the signal transduction pathway linking m3 with sweating. This factor
may be acetylcholine, given the ability of cholinergic agonists to maintain secretory responsiveness in denervated glands (Grant et al.,
1995).
We generated mice that cannot make NE because of the inactivation of
the DBH gene, which is essential for the conversion of dopamine (DA) to
NE (Thomas et al., 1995). Although most DBH / mice die during
gestation, they can be rescued pharmacologically until birth. After
birth, they develop into viable adults without further intervention
(Thomas et al., 1995). The DBH / mice have almost no NE beginning
at P2, which is when the sweat gland primordia begin to develop and
before innervation by noradrenergic fibers. Thus, if NE is necessary to
induce SGF expression, which in turn causes switching, then the switch
should not occur in DBH / mice, and they should not sweat in
response to cholinergic agonists.
MATERIALS AND METHODS
Animals. The mice were fourth and fifth generation
hybrids of C57BL/6J and 129/SvCPJ. DBH +/ females were mated with DBH / males and treated with 10 µg/ml each of phenylephrine and isoproterenol (Sigma, St. Louis, MO) from embryonic day (E) 9.5-14.5, and 1 mg/ml L-threo-3,4-dihydroxyphenylserine (DOPS; a
generous gift from Sumitomo Pharmaceuticals, Osaka, Japan) from E14.5
to birth in the maternal drinking water. TH +/ males and females were
mated, and the females were treated with 1 mg/ml DOPS from E 9.5 to
birth. The pups were genotyped by PCR at 3-4 weeks of age. DBH +/
mice were used as controls because NE levels are normal in these mice
(see Fig. 1), and the number of glands responding to pilocarpine did
not differ between DBH +/+ and DBH +/ adult mice. Adults used in
these experiments ranged in age from 2 to 4 months.
Fig. 1.
Catecholamine (CA) levels. A, Whole
homogenized neonates either on the day of birth (P1) or
the next day (P2). Results were combined for DBH +/
neonates because they did not differ between the days. Levels are the
mean ± SEM of 4-6 pups for each condition. B,
Footpads from DBH +/+, DBH +/, and DBH / adult mice. Levels are
the mean ± SEM of 5-6 footpads for each genotype.
Asterisks indicate that the levels were below the limit
of detection.
[View Larger Version of this Image (18K GIF file)]
Catecholamine measurements. The methods described in Thomas
et al. (1995) were used. Briefly, footpads and neonates were frozen on
dry ice and stored at 70°C. Footpads were sonicated; neonates were
first homogenized in 4.5 ml of perchloric acid buffer/gram and then 0.4 ml was sonicated. All samples were maintained at 4°C until injection
into the HPLC. Sonicates were centrifuged for 10 min at 18,700 × g. A 200 µl aliquot of supernatant was added to 20 mg of
acid-washed alumina and 800 µl of Tris/EDTA buffer and rotated
overnight. The alumina was washed twice with 1 ml of distilled water,
and then catecholamines were extracted with perchloric acid buffer. The
HPLC was run at a flow rate of 1 ml/min, and an injection volume of 20 µl was used. The working potential of the electrochemical detector
(BAS LC-4C) was +0.8 V, and the full scale sensitivity was 5 nA.
Quantification of catecholamines was performed by comparing the peak
heights of unknowns to those of known quantities of catecholamine
standards using an HP 3393A integrator. The lower limit of detection
was 20 pg. Protein was determined using Bio-Rad protein microassay (Bio-Rad, Hercules, CA).
Agonist-induced sweat response. The agonist-induced sweat
response was obtained by first anesthetizing the animal with a ketamine (Fort Dodge Laboratories, Fort Dodge, KA)/xylazine (Phoenix
Pharmaceutical) mixture (0.66 ml ketamine/0.22 ml xylazine in 10 ml
PBS; dose 0.025 ml/gm). The left hind paw was then painted with an
iodine (Sigma) solution (5 mg/100 ml ethanol) followed by a coat of
starch solution (5 gm/10 ml mineral oil). Pilocarpine (Sigma) was
administered subcutaneously into the foot (50 µg), and 2 min after
injection a photograph was taken of the sweat response.
Nerve-evoked sweat response. The nerve-evoked sweat response
was obtained by anesthetizing the animal with the ketamine/xylazine mix
and then isolating the sciatic nerve in the left hind leg. The foot was
painted with the iodine and starch solutions. The nerve was then placed
on a bipolar stimulating electrode (provided by A. Berger, University
of Washington) for 2-3 min and stimulated at 15 V, 5.5 Hz (Stevens and
Landis, 1987). A picture of the nerve-evoked sweating was taken, and
then atropine (Sigma) was administered intraperitoneally at 0.125 gm/kg. The foot was wiped clean, and the iodine/starch solutions were
reapplied. The nerve was then stimulated a second time at the same
conditions for 3-4 min, and another picture was taken to quantitate
the sweat response after administration of atropine.
Immunohistochemistry. The footpads were fixed in 10%
neutral buffered formalin (Richard-Allen, Richland, MI). They were
embedded in paraffin blocks and cut into 10 µm sections. Before
immunohistochemistry, the sections were deparaffinized and hydrated,
and endogenous peroxidases were inactivated in 0.6%
H202 for 15 min. Nonspecific binding was
blocked with 1% BSA/3% goat serum for 1 hr (Vector Labs, Burlingame,
CA). The primary antibodies against VIP (Incstar, Stillwater, MN) and
TH (Eugene Tech, Ridgefield Park, NJ) were both generated in rabbits.
The sections were incubated at 4°C with the primary antibodies TH
(1:1000) or VIP (1:1000) in incubation buffer (1% BSA/0.5% Triton
X-100, 1% goat serum in PBS) for 16-20 hr. The slides were rinsed
with incubation buffer and then incubated with the secondary
biotinylated goat-anti-rabbit antibody (Vector Labs, Burlingame, CA)
diluted 1:200 in the same buffer for 1 hr. The sections were rinsed
again with buffer and incubated 15-30 min with
streptavidin-horseradish peroxidase (Zymed, San Francisco, CA) at 1:20
dilution. After two more rinses, the immunoreactivity was visualized
using an aminoethyl carbazole substrate kit (Zymed). The sections were
mounted in Aquamount (Ler-ner Labs, Pittsburgh, PA). Adjacent
sections were treated as above except that incubation with the primary
antibody was not performed. None of these control sections exhibited
peroxidase immunoreactivity.
RESULTS
Agonist-induced sweating and the development of the
sweat response
Because most mice lacking NE (DBH / or TH /) die in
utero (Thomas et al., 1995; Zhou et al., 1995), all homozygotes
studied were rescued pharmacologically by supplying either adrenergic agonists or the NE precursor DOPS in the maternal drinking water beginning at E9.5 and continuing until birth. With this paradigm, whole
pup NE levels were 19% of normal on the day of birth (P1) and very
close to the limit of detection for NE 1 d later (<5% of normal)
(Fig. 1A). Epinephrine was below the
limit of detection in DBH / neonates (P1 or P2), whereas DA was
significantly elevated to about half the level of NE found in controls.
Thus NE falls to below the limit of detection within 48 hr of birth in
DBH / neonates. Adult footpads had similar catecholamine levels. NE levels did not differ between DBH +/+ and DBH +/ footpads, whereas NE
was below the limit of detection in DBH / footpads (Fig. 1B). DA was present in DBH / footpads at ~40%
of the normal NE level, whereas DA was below the limit of detection in
DBH +/+ and DBH +/ footpads. DBH +/ mice were routinely used as
controls, because in addition to having normal levels of NE their sweat response did not differ from adult wild-type mice.
To ascertain whether NE-deficient mice could develop a normal sweat
response, adult DBH / mice and heterozygous controls were injected
with pilocarpine, a cholinergic agonist, and the response was measured
by counting the number of glands that secreted amylase using the
iodine-starch method (Wada and Takagaki, 1948). The hind foot was
washed and painted with an iodine solution followed by a starch
solution. Then a local injection of pilocarpine was administered, and a
picture of the hind foot was taken 2 min later. Pilocarpine elicited a
sweat response in mice of both genotypes (Fig. 2). The
number of black spots, each representing the secretion from a single
gland, was determined. Although sweat responses were obtained on the
digits as well as footpads, we focused on the six footpads for
quantitation. There was no significant difference between adults of the
two genotypes in the number of responsive glands (Fig.
3).
Fig. 2.
Pilocarpine-induced sweat response.
A, Adult DBH +/ mouse. B, Adult DBH
/ mouse. C, P21 DBH +/ mouse.
D, P21 DBH / mouse. Iodine/starch solutions were
painted onto the left hind paw, the foot was injected with 50 µg
pilocarpine, and the sweat response was photographed 2 min after
injection. The black dots are the sweat response of
individual glands.
[View Larger Version of this Image (149K GIF file)]
Fig. 3.
Development of the sweat response in DBH +/ and
DBH / mice. A, The sweat response was induced using
50 µg pilocarpine and detected with the iodine/starch
method. No sweat response was detected in either DBH +/ or DBH /
mice at P11, but note the fivefold difference between
the genotypes at P21 (t test;
p = 5 × 10
4). These data reveal
that the development of the sweat response in DBH / animals is
delayed ~1-2 weeks. Once they reach adulthood, however, the sweat
response is fully developed in both genotypes. Error bars represent SEM
(n = 4 or 5 animals/genotype/age).
B, The sweat response of the DBH +/ and DBH / mice
as a function of weight, ages P11-adult. The general runting of the
DBH / mice is not responsible for the delayed sweat response. At 10 gm, the DBH / mice show a significantly lower (t
test; p = 0.002) number of responsive glands than
DBH +/ mice. As the animals become larger (and older), both genotypes
exhibit a comparable sweat response.
[View Larger Version of this Image (19K GIF file)]
We also examined the development of the sweat response in both groups
of mice as shown in Figure 3. At P11 and P14 either no responsive sweat
glands or very few responsive sweat glands were detected in either
group, but by P21 there was a robust response in DBH +/ mice that was
about half that observed in adults (Figs. 2, 3A). The
NE-deficient mice showed a significant lag in the emergence of a sweat
response that was significant at P21. The normal growth spurt that
usually begins at ~3 weeks of age is delayed 1-2 weeks in DBH /
mice; consequently they are ~60% of normal weight at 4 weeks of age
but they ultimately grow to ~85% of normal size (Thomas et al.,
1995). The delay in sweat response in DBH / mice might reflect
either their growth retardation, or more interestingly, NE might
facilitate the development of an adult sweat response. We have also
plotted the development of the sweat response as a function of body
weight (Fig. 3B), which demonstrated that the developmental
lag of the DBH / mice was less apparent. DBH / mice weighing
~10 gm, however, still had a significantly lower number of responsive
glands than the DBH ± mice at this weight, even though the DBH
/ mice were older (t test; p = 0.002).
The noradrenergic neurons of DBH / mice produce DA by default.
Consequently, if sweat glands have appropriate DA receptors, they might
be responding to DA instead of NE. Alternatively, DA might act as a
weak agonist at adrenergic receptors. Because of these considerations,
we also tested mice that lack TH, the first enzyme in the
catecholaminergic pathway. These mice lack both DA and NE. The few that
are born become runted and die a few weeks after birth (Zhou et al.,
1995). We tested four TH / mice that survived to P21; the largest
two (each 5 gm) showed a fairly normal sweat response on the digits,
but only a few glands on the pads responded to pilocarpine (Fig.
4). The other two TH / mice did not elicit a sweat
response; however, their weight (3.5 gm) was below that at which even
control mice (8-10 gm at P21) elicited a response (Fig.
3B). Because the TH / mice were expected to die within
several days, events not related to the absence of NE might account for
the poorer sweat response as compared with DBH / mice at P21.
Fig. 4.
The pilocarpine-induced sweat response of TH /
mice. A, TH +/ mice at P21 respond both on the
footpads and the tips of the digits (white arrows).
B, The TH / mice make no catecholamines yet can be
induced to sweat using pilocarpine. The P21 TH / mice that were
tested exhibited sweating mainly on the tips of the digits, and a few
glands on the footpads also responded (black arrows).
[View Larger Version of this Image (117K GIF file)]
Nerve-evoked sweat response
The previous experiments demonstrated that the sweat glands of DBH
/ mice have functional cholinergic receptors because they respond
to pilocarpine. To determine whether the neurons that innervate the
sweat glands release acetylcholine, we examined nerve-evoked sweating.
Electrostimulation of the sciatic nerve elicits sweating in cats by
release of acetylcholine (Dale and Feldberg, 1934). In rats, the
nerve-evoked sweat response is blocked by muscarinic cholinergic
antagonists and is unaffected by adrenergic antagonists, demonstrating
that it is a cholinergic event (Stevens and Landis, 1987). The sweat
response of DBH / mice to nerve stimulation was indistinguishable
from that of DBH +/ controls (Fig. 5). Moreover,
administration of atropine, a muscarinic cholinergic antagonist, after
the first response blocked a subsequent response to electrostimulation
in mice of both genotypes (Fig. 5). In the absence of atropine, a
second response was nearly as strong as the first.
Fig. 5.
The nerve-evoked sweat response in adult DBH +/
and DBH / mice. The sciatic nerve of the left hind paw was
stimulated by an electrode for 2-3 min, atropine was administered, and
the nerve was stimulated a second time for 3-4 min. There were no
significant differences in the number of responsive glands between the
genotypes. Error bars represent SEM (n = 4 for each
genotype).
[View Larger Version of this Image (15K GIF file)]
Innervation of the developing sweat glands
The morphology of the sweat glands of the DBH +/ and DBH /
mice was indistinguishable (Fig.
6A,B). The switch from a noradrenergic to cholinergic phenotype in rats is associated with a downregulation of
TH immunoreactivity and the appearance of ChAT and the neuropeptides VIP and CGRP (Leblanc and Landis, 1986; Landis et al., 1988; Stevens and Landis, 1988). To characterize the neuronal switch in mice, we
performed immunocytochemistry on foot pads from mice at various ages.
Our experiments revealed that there was a progressive gain in TH and
VIP immunoreactivity in mice between P14 and adult (Fig. 6). VIP was
faintly detectable at P14 in animals of both genotypes. At P21, VIP
immunoreactivity was as strong in the DBH / as in the DBH +/
mice, although the sweat responses at this age were dissimilar (Fig.
3A). TH immunoreactivity was faint but detectable at P14 in
DBH +/ mice, and even less apparent in the DBH / mice at P14. At
P21, levels of immunoreactivity for TH were elevated to adult levels
and similar between the genotypes.
Fig. 6.
The development of the innervation of the sweat
glands of DBH +/ and DBH / mice. Hematoxylin and
eosin-stained adult glands show a comparable morphology. The expression
of VIP and TH is similar in mice of both genotypes. Footpad sections of
both DBH +/ and DBH / mice show a large increase in
immunoreactivity for VIP and TH from age P14 to P21 and is strongest in
adult sections. A, B, Hematoxylin and
eosin-stained adult footpads; C-F, footpads from P14
mice stained with antisera to TH and VIP; G-J, footpads from P21 mice stained with antisera to TH and VIP; K-N,
footpads from adult mice stained with antisera to TH and VIP.
[View Larger Version of this Image (133K GIF file)]
DISCUSSION
The acquisition of the cholinergic phenotype in rats is dependent
on the production of SGF, which presumably is induced by some signal
from the neurons innervating the glands (Landis and Keefe, 1983; Landis
et al., 1988). The secretory response of the sweat gland is dependent
on the neurons innervating the glands (Grant et al., 1995), but the
morphological development of the glands is not compromised by the
absence of innervation (Yodlowski et al., 1984). Although muscarinic
receptors are expressed at normal levels on the sweat glands even when
there is no innervation (Grant et al., 1991), innervation of the glands
is the critical factor for the acquisition of the
acetylcholine-mediated sweat response. Thus, it is reasonable to
speculate that products released from nerves innervating the sweat
glands are responsible for the induction of SGF and that NE could be a
candidate. That -adrenergic antagonists block the induction of SGF
in sweat gland/sympathetic neuron cocultures is consistent with this
postulation (Habecker and Landis, 1994). Also, activation of adenylyl
cyclase by forskolin is sufficient to induce the production of SGF
(Habecker and Landis, 1994), suggesting that NE might act by inducing
cAMP signaling through -adrenergic receptors. This same study,
however, indicated that an 1-adrenergic antagonist
blocked induction of SGF, raising the question of whether these drugs
were having nonspecific inhibitory effects, because -adrenergic
stimulation was expected to be sufficient.
Our results indicate that NE is not necessary for the acquisition of a
mature sweat response in the mouse. Cholinergic agonists stimulate a
response in the DBH / mice, and a nerve-evoked sweat response can
be blocked with a cholinergic antagonist. Immunohistochemistry shows
that TH increases dramatically between P14 and adult, as does the
neuropeptide VIP. The major difference in the sweat responsiveness between the DBH / mice and normal mice is a developmental delay that is pronounced at P21, but this does not affect the expression of
VIP or TH. The delay may be partly attributable to the general growth
retardation of DBH / mice, but there is still an effect when the
data are plotted as a function of mouse weight rather than age (Fig.
3B).
Adult DBH / mice have no detectable NE in footpads, as measured by
electrochemical detection after HPLC (Fig. 1B). NE
decays to undetectable levels within 48 hr of birth (Fig.
1A). Thus, even though the DBH / fetuses were
rescued to birth by treating the mother with DOPS, no NE would be
present after birth when the noradrenergic processes begin to innervate
the developing sweat glands around P4. We cannot completely rule out
the possibility, however, that NE present at the time of birth
instructs the few sweat gland progenitor cells present to eventually
release SGF. Sweat glands from normal rats that have presumably been
exposed to circulating NE in vivo, however, do not produce
SGF if the innervation to these glands is prevented by
6-hydroxydopamine treatment from P1 to P7 (Habecker and Landis, 1994).
Of greater concern is the possibility that DA might substitute for NE,
either as a weak agonist acting on adrenergic receptors or as an
agonist acting on dopaminergic receptors. The amount of DA released
from nerve terminals of DBH / mice is probably similar to the
amount of NE that would normally be released in wild-type animals. The most compelling argument that switching does not require NE or DA is
that some sweat glands respond in young TH / mice that produce
neither NE nor DA. It is not clear why relatively more glands responded
in the digits than the footpads of TH / mice (Fig. 5). Thus, we
conclude that NE is not essential for induction of SGF and transmitter
switching even though it does seem to facilitate the switch.
Previous studies of phenotypic switching of the neurons innervating the
sweat glands were performed in the rat. In that system, immunoreactivity for TH decreases as that for VIP increases. Our work
in the mouse, however, demonstrates a gradual increase in the
expression of both TH and VIP between P7 and P21, although the glands
are functionally cholinergic. Guidry and Landis (1995) demonstrated
that TH-immunoreactive fibers innervate the developing sweat glands as
early as P4, and the number of TH-positive fibers increases
dramatically by P14. Rao et al. (1994) demonstrated that substantial TH
immunoreactivity is still present in sweat glands of adult mice;
however, catecholamine histofluorescence that is present at P4 largely
disappears by P21 in mice (Guidry and Landis, 1995). Thus although
levels of TH remain high in mice, catecholamine synthesis is switched
off as cholinergic synthesis is switched on, similar to that observed
in rats (Landis and Keefe, 1983).
If NE is not essential for induction of SGF, what neuron-derived factor
might act in concert with NE and promote switching in its absence? One
possibility is ATP. Catecholamines are packaged in synaptic vesicles
along with ATP and they are co-released. A number of purinergic
receptors have been characterized recently (Surprenant et al., 1995)
and at least one of them (P2X4) is expressed in epithelial
tissues (Surprenant et al., 1996), but the presence of purinergic
receptors in developing sweat glands has not been determined yet.
Alternatively, neuropeptides are produced and released by most
sympathetic neurons in addition to NE and ATP, so they are also
potential candidates. Because NE seems to potentiate development of the
sweat response, our results suggest that innervation of the sweat
glands may normally activate at least two pathways that act together to
induce SGF. In the absence of NE, the second pathway can lead to
complete switching but with a delay of up to 2 weeks. It will be
interesting to determine the nature of the second signal, the signal
transduction pathway that it activates, and whether it is also
dispensable for switching if NE is present.
FOOTNOTES
Received Oct. 15, 1996; revised March 3, 1997; accepted March 19, 1997.
This work was supported in part by National Institutes of Health Grant
HD-09172. We thank B. Marck and A. M. Matsumoto for the catecholamine
measurements, C. J. Quaife for advice with the immunocytochemistry, G. Froelick for help with the histology, M. Bellingham and S. C. Baraban
for their helpful suggestions, and Sumitomo Pharmaceuticals for their
generous gift of DOPS.
Correspondence should be addressed to Dr. Richard D. Palmiter, Howard
Hughes Medical Institute, Box 357370, Department of Biochemistry,
University of Washington, Seattle, WA 98195-7370.
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