1. No category

From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
1991 78: 1936-1941
Anemia and mast cell depletion in mutant rats that are homozygous at
"white spotting (Ws)" locus
Y Niwa, T Kasugai, K Ohno, M Morimoto, M Yamazaki, K Dohmae, Y Nishimune, K Kondo and Y
Kitamura
Updated information and services can be found at:
http://www.bloodjournal.org/content/78/8/1936.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
Anemia and Mast Cell Depletion in Mutant Rats That Are Homozygous at “White
Spotting (Ws)”Locus
By Yoshiki Niwa, Tsutomu Kasugai, Kyoko Ohno, Masahiro Morimoto, Masaru Yamazaki, Kayoko Dohmae,
Yoshitake Nishimune, Kyoji Kondo, and Yukihiko Kitamura
Mice possessing two mutant alleles at the W or SI locus are
anemic and deficient in mast cells. These mouse mutants
have black eyes and white hair. Because homozygous mutant
rats at the newly found white spotting (Ws) locus were also
black-eyed whites, the numbers of erythrocytes and mast
cells were examined. Suckling Ws/ Ws rats showed a severe
macrocytic anemia and were deficient in mast cells. When
bone marrow cells of normal ( + / + ) control or Ws/Ws rats
were injected into C3H/ He mice that had received cyclophosphamide injection and whole-body irradiation, remarkable
erythropoiesis occurred in the spleen of / + marrow recipi-
ents but not in the spleen of Ws/Ws marrow recipients.
When skin pieces of Ws/ Ws embryos were grafted under the
kidney capsule of nude athymic rats, mast cells did develop
in the grafted skin tissues. Therefore, the anemia and mast
cell defidency of Ws/ Ws rats were attributed to a defect of
precursors of erythrocytes and mast cells. Because the
magnitude of the anemia decreased and that of the mast cell
deficiency increased in adult WslWs rats, this mutant is
potentially useful for investigations about differentiationand
function of mast cells.
0 1991 by The American Society of Hematology.
HE DOMINANT SPOTTING (w)locus influences
the coat color of mice.’.’ Mice of W/+ or W / +
genotypes have one or two well-defined white spots. Although the rest of the coat of W/+ mice is normal, that of
W / + mice is apparently diluted. Many mutant alleles
other than Wand W”have been reported at the W locus.
Mice possessing two mutant alleles at the W locus, such as
W / K W/W”, and W“/Wmice, are black-eyed whites.’,’ In
addition to the depletion of melanocytes in the skin, W/W,
W/W, and W I W ” mice show hypoplastic anemia, depletion of mast cells, and germ cells.’”
The W locus was shown to be identical with the c-kit
p r o t o - o n ~ ~ g e n eThe
. ~ ’ ~c-kit gene is the normal cellular
homologue of the v-kit oncogene and encodes a receptor
tyrosine kinase.6-8Recently, a ligand for the receptor
encoded by the W (c-kit) locus was
Because
the ligand is encoded by the steel (Sl) locus of mice,9’12
homozygous or double-heterozygous mutants at either the
W (c-kit) or SI locus have the same phenotype.lS2Melanocytes, erythrocytes, mast cells, and germ cells are also
depleted in the SI mutant mice. As supposed from the
molecular nature of the W (c-kit) and $1 loci, depletion of
melanocytes,” erythrocyte^,'^ mast cells,3and germ cellsI5in
the W (c-kit) mutant mice is due to a defect of precursor
cells, whereas the depletion of melanocyte^,'^ erythrocytes,16mast cells,” and germ
in the S1 mutant mice
is due to a defect of the stromal cells that support the
differentiation.
The v-kit oncogene was first identified in feline fibrosarcoma cells: and the c-kit proto-oncogene has been cloned
in humans and mice.’r8 Although the mutation at the c-kit
locus has been reported only in mice, rats are used as
frequently as mice as laboratory animals. If mutant rats at
the c-kit locus are found, they will be useful tools for
studying differentiation of hematopoietic progenitor cells
and function of mast cells. Mast-cell-deficient rats appear
to be more useful than mast-cell-deficient mice, because
mast cells from various tissues of rats are better characterized than those of miceZaand because some experiments are
more easily performed by using rats due to their bigger size.
We present evidence that the rat mutation has a similar
phenotype to the WIW mouse.
+
T
From the Laboratory of Experimental Animals, Yagi Memorial
Park, Kani-gun; and the Department of Patholo@, Medical School
and the Research Institute for Microbial Diseases, Osaka University,
Osaka, Japan.
Submitted April 2,1991; accepted June 10, 1991.
Supported by grants from the Ministry of Education, Science and
Culture, the Ministry of Health and Welfare, the Hoansha Foundation,
the Cell Science Research Foundation, and the Hokuriku Seiyaku
Allergy Award.
Address reprint requests to Yukihiko Kitamura, MD, Department of
Pathology, Osaka University Medical School, Yamada-oka 2-2, Suita,
Osaka, 565, Japan.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C.section 1734 solely to
indicate this fact.
0 I991 by The American Society of Hematology.
0006-4971I91 17808-0008$3.00/0
1936
MATERIALS AND METHODS
Animals. The BNlfMai (hereafter BN) strain rat was originally
obtained from Dr J. Yamada (Kyoto University, Kyoto, Japan) and
was maintained by brother-sister mating at the Laboratory of
Experimental Animals (Yagi Memorial Park, Kani-gun, Japan)
since 1984. In the spring of 1987, a male rat with diluted coat color
and a large white spot in the abdominal wall was found in this
inbred colony. The male rat was crossed to normal (brown) BN
females; offspring with the mutant phenotype was obtained and
was maintained thereafter by the repeated backcrosses to the
normal BN rats. The Donryu strain of rats was established by Dr H.
Sat0 (Japan Rat Co Ltd) and was maintained by brother-sister
mating in Yagi Memorial Park. Nude athymic rats were maintained
as a closed colony in the Research Institute for Microbial Diseases
(Osaka University, Osaka, Japan).
WB-(W/+, SI/+, + I + ) and C57BL/6-(W“/+, SId/+, + I + )
mice were maintained at the Department of Pathology (Osaka
University). Embryos of either WIW or SIISld genotype were
produced by crossing the previously mentioned mutant mice.
Embryos were harvested 17 to 19 days after coitum, and those
showing severe anemia were considered to be of the Wl W‘ or SIISld
genotype. Mice of the C3HlHe strain were purchased from the
Shizuoka Laboratory Animal Center (Hamamatsu, Japan). For
routine histologic examination, animals were killed by overinhalation of ether; tissues were fixed with Carnoy’s fluid; ordinary
paraffin sections were stained with either hematoxylin and eosin or
alcian blue.
Erythrocytes and mast cells. Rats were anesthetized by ether
and killed by decapitation. Blood samples were obtained, and a
Blood, Vol78, No8 (October 15). 1991: pp 1936-1941
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
1937
MAST CELL-DEFICIENT RATS
hemocytometer was used to determine numbers of erythrocytes.
Hematocrit values were determined by a micro-capillary centrifuge. Pieces of the dorsal skin were fixed by Carnoy's fluid and
embedded in paraffin. Sections (4 pm thick) were stained with
alcian blue. The number of mast cells was counted under the
microscope. and was expressed as the number per centimeter of
skin.'
Bone " o w rrunJplanrarion. There were some difficulties in
using rats as the recipients of bone marrow cells in the present
experiment. ( I ) Because homozygous mutant rats and normal
control rats were obtained as F2generation between two different
inbred strains, their genetic background was heterogenous. Although genetic resistance against allogeneic bone marrow cells has
been investigated intensively in mice;'.'' there is no information
about the genetic resistance in rats. (2) Whole-body irradiation
doses as high as 14 Gy do not inhibit the development of
endogenous spleen colonies in ratsB Because the poor growth of
the mutant bone marrow cells was anticipated, it was considered to
be difficult to distinguish small endogenous colonies and exogenous
colonies derived from the bone marrow of mutant rats. (3)
Numbers of exogenous spleen colonies in rats are significantly
influenced by the recipients' age." Therefore, we used C3HIHe
mice as recipients of rat bone marrow cells according to the
method described by Himei.' C3HIHe mice that were 4 months
old received an intraperitoneal (IP) injection of cyclophosphamide
(100 mglkg) and lethal whole-body irradiation (7.8 Gy) before the
bone marrow transplantation. Bone marrow cells of rats were
obtained from femurs and tihias according to the method described
previously." The hone marrow cells were suspended in Eagle's
medium, and 5 x IO' cells were injected into the lateral tail vein of
the recipients within 3 hours after the irradiation. The recipients
were killed 6 days after the transplantation, and spleens were
harvested, weighed, and fixed in Bouin's fluid. Spleens were cut
along the longitudinal axis and embedded in paraffin. Sections
were stained with hematoxylin and eosin and were examined under
the microscope.
Skin rrunsplunrurion. Pieces of the skin were obtained from
mouse embryosof either WIN."orS/ISPgenotype and were grafted
under the kidney capsule of congenic +I+ mice. Anemic rat
embryos that resembled WIN." and S//SP' embryos were identified:
skin pieces were obtained and grafted under the kidney capsule of
nude athymic rats. During the transplantation procedure. the
recipients were anesthetized with an IP injection of sodium
pentobarbital (Pitman-Moore, Inc, Washington Crossing, NJ). The
recipient mice and rats were killed 5 weeks after the transplantation. and the grafted skin pieces, which looked like dermal cysts.
were harvested. The genotypes of donors were confirmed by the
white color of hairs that grew in the cystic cavity. The skin grafts
were fixed with Carnoy's fluid, and the paraffin sections were
stained with alcian blue to determine the number of mast cells.
RESULTS
Coat color dilution of mutant BN rats was similar to that
of W / + mice, and the large ventral spot was comparable
with that of Wl+ mice (Fig 1). When the mutant rats were
mated to normal (brown) BN rats, the ratio of normal-tospotting offspring was 1:l (Table 1). Spotting BN rats were
mated together; the ratio of normal-to-spotting offspring
was approximately 1:2 (Table 1). Because the litter size of
the latter cross (4.3 2 0.3, n = 13)was significantlysmaller
than that of the cross between normal BN rats (6.02 0.3,
n = 13). the homozygotes at the mutant locus appeared to
be lethal in the BN genetic background. In fact, some
Fig 1. Coat color pattern in
ratsof +I+.Wsl+.and WsfWs
genotypes. The W s / + rat shows
coat color dilution and a large
white spot in the abdominal wall.
+I+
MI+ MIM
anemic embryos were detectable when spotting BN females
were killed between 15 and 17 days after crossing to
spotting BN males. Male spotting BN rats were matcd to
Donryu females, and the resulting F,hybrids with spotting
wcrc matcd together. As shown in Table 1, black-eyed
white rats resembling either W / W or SI/Sld mice were
obtained (Fig 1). Hereafter, we designated the mutant
allele as whitc spotting (Ws).
When eyes of black-eyed white rats were histologically
examined, pigment cells were present in the retina but not
in the choroid (Fig 2). Because the histologic features of the
eyes were identical to those of WIW and Sl/Si" mice,' we
considered them to be homozygous WslWs rats. The
number of WYIWSrats recognized after birth was significantly less than the expected number, probably due to
intrauterine death (Table 1). However. the WY/WFrats that
survived 30 days usually grew up and appeared to be
healthy over 1 year.
As shown in Table 2, WslWs rats showed a severe
macrocytic anemia and Wsl+ rats showed a mild anemia.
The anemia of Ws/Ws rats tended to ameliorate 10 weeks
after birth.
To investigate the cause of the anemia, bone marrow
cells of WslWs and +/+ rats were injected into the
C3H/He mice that had received the cyclophosphamide
injection and the whole-body irradiation. The weight of
spleens was significantlysmaller in the recipients of U!s/Ws
marrow cells than in the recipients of + / + marrow cells
(Table 3). Because rat bone marrow cells were injected into
mouse recipients, there is a possibility that the increase in
the spleen weight may be due to graft-versus-host or
host-versus-graft reaction. Therefore, histologic sections of
all spleens were examined. Only one endogenous spleen
colony was found in eight spleens of the control C3H/He
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
NlWA ET AL
1938
Table 1. Segregationof Mutant Rats With White Spotting
No. of Rats With Each PhenotypeIgenowpe)
Normal
Spotting
Parentsand Cross
Presumed
Genotypeof Parents
(+I+)
lWSl+l
Normal BN x normal BN
Normal BN x spotting BN
Spotting BN x spotting BN
Normal Donryu x spotting BN
Spotting F , x spotting F ,
Black-eyedwhite F , x black-eyed white F,
EN-+/+ x “ + I +
E N - + / + x BN-WSl+
BN-WSl+ x BN-WSl+
Donryu-+I+ x EN-Wsl+
F,-WSl+ x F,-WSl+
F,-WslWs x F,-WslWs
541
120
0
43
85
121
68
53
186
0
0
34
Black-Eyed
White (WslWsl
0
0
0
0
33’
75
Total
541
241
102
96
304
75
‘P < .01 when compared with the expected value by the x y test.
micc that rcccivcd thc cyclophosphamide injection and
irradiation alonc. No hcmatopoicsis was dctcctablc in the
othcr scvcn splccns of the control C3H/Hc micc (Fig 3A).
When bonc marrow cells of Wsl Ws rats wcrc injectcd, vcry
small foci of crythropoicsis wcrc observed in thc rcd pulp of
thc rccipicnts’ splccn (Fig 3B). By contrast, t h e rcd pulp
was occupicd by proliferating hcmatopoictic cells whcn
bonc marrow cclls of +/ + rats wcrc transplantcd (Fig 3C).
Most of thc hcmatopoictic cclls wcrc crythroblasts of
various differentiation stages (Fig 3D), but somc mycloid
cclls and mcgakaryocytcs were also observed. Although
histologic fcaturcs of thc rcd pulp wcrc markcdly influenced by the origin of transplanted bonc marrow cclls. the
histologic fcaturcs of thc white pulp were comparahlc
hctwccn spleens of the C3H/Hc micc that rcccivcd + / +
cclls and thosc of thc C3H/Hc micc that rcccivcd WslWs
cells. In both cascs, ccll divisions wcrc scarcely detcctablc in
the white pulp.
The numbcr of mast cells in the skin of +/+, Ws/+,
and
WslWs rats were counted at various ages. Although small
numbers of mast cells were found in thc skin of Ws/Ws rats
by 4 weeks after birth, practically no mast cclls wcrc
detcctablc 10 wccks after birth (Tabic 4). A moderate
decrease of the mast ccll numbcr was obscrvcd in thc skin
of Ws/+rats (Tablc 4). No mast cells wcrc dctcctablc in the
splccn, bonc marrow, liver, stomach, small and largc
intcstines, lung, and brain of Ws/Ws rats.
Picccs of thc skin of ancmic rat cmbryos wcrc transplanted undcr thc kidncy capsulc of nudc athymic rats.
Nude athymic rats wcrc uscd as rccipicnts hccause thc
congcnic rccipicnts wcrc not availahlc in thc present
brccding procedure. As controls. skin picccs of W / W and
SI/Sr‘ mousc cmbryos wcrc graftcd under the kidncy
capsulc of thc congcnic + /+ micc. Mast cclls dcvclopcd in
thc skin pieces grafted from W ~ / Wrat
T cmbryos or from
W / W mousc cmbryos. but not in thc skin picccs grafted
from SIISr’ mousc cmbryos (Tablc 5).
Rats of thc WY/WT
gcnotypc showed dcplction of mclanocytcs, erythrocytcs, and mast cclls. The magnitude of
mast-ccll dcficicncy in Ws/Ws rats was comparahlc with the
valucs obscrvcd in W / W and SIISI‘’ micc. Although both
WIW’and SIISI” micc arc stcrilc duc to dcplction o f germ
cells, tcstcs and ovarics of Ws/Ws rats containcd normal
numbers of germ cells (Fig 4). Somc offspring of thc WsI Ws
gcnotypc wcrc obtaincd from crosscs hctwccn malc and
fcmalc Wy/Ws rats (Tablc 1).
DISCUSSION
Rats of thc WSIWTgcnotypc wcrc black-cycd whitcs;
pigmcnt cclls wcrc prcscnt in thc rctina hut not in the
Table 2. Number of Erythrocytes and Mean Corpuscular Volume in
Rats with + I W s / + , and Wsl Ws Genotypes
+.
Age
(wk)
2
Genotype
+I+
Wsl +
WSlWS
4
10
+I+
wslws
Fig 2. Depletion of pigment cells in the choroid (C) but not in the
Wins (R) of the eye of a W s l Ws mt. n e conhol is the eye of a + 1 +
rat. Arrows show the nucleus of the pigment epithelium of the retina.
Hematoxylin-eosinoriginal magnification x Boo.
50
Mean Corpuscular
Volume (IL)’
4.38 c 0.9 (8)
3.25 c 0.16 ( 8 ) t
2.02 c 0.11 (1217
71 c l(8)
84 f 3 (7)t
122 c 6 (10)t
+I+
5.32 f 0.30(7)
Wsl +
WSlWS
4.99 c 0.9 (7)
2.81 t 0.23(9)t
66 f 3 (6)
77 c 2 (6)$
102 f 4 (61t
+I+
7.65 f 0.37 (6)
7.36 c 0.24 (6)
5.97 ? 0.15 (6)t
60 c 2 (6)
64 f 2 (6)
72 c 2 (61t
+I+
8.74 f 0.28 (6)
6.53 0.50 (6)t
6.31 ? 0.43 (6)t
58 c 2 (6)
72 f 4 (6)*
73 r 3 (6)t
Wsl +
WSlWS
h
No.of Ewhrocyles
IXl0”lL)’
Wsl+
WSlWS
=
.Mean 2 SE; the number of rats is shown in parentheses.
t P < .01 when compared with values of + I + rats by the t-test.
SP < .05when compared with values of + I + rats by the t-test.
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
MAST CELL-DEFICIENT RATS
1939
Table 3. Poor Growth of Hematopoietic Stem Cells of Wsl Ws Rats
in the Spleen of C3HlHe Mice That Had Received Cyclophosphamide
Injection and Whole-Body Irradiation
Genotype of Donors
None
44 k 6 (8)
WSlWS
43 f 7 (12)
77 6 (12)t
+/+
*Mean
Spleen Weight (ma)’
k
Table 4. Number of Mast Cells in the Skin of + I +, W s l + , and
Wsl Ws Rats at Various Ages
Age
(wk)
2
*
SE; the number of spleens is shown in parentheses.
tP < .01 by the t-test when compared with values of recipients that
+I+
Wsl +
WSlWS
4
+I+
Wsl f
had not received any bone marrow cells.
choroid of the black eyes. WslWs rats showed macrocytic
anemia and mast cell depletion. However, mast cells did
develop when skin pieces of WslWs embryos were grafted
under the kidney capsule of nude athymic rats, suggesting
that cells in the skin of WslWs rats can normally support the
differentiation of mast cells. Because mast cells developed
in the skin pieces grafted from wlwmouSe embryos but
did not develop in the Skin pieces grafted fromSl/Sldmouse
embryos, the Ws mutation of the rats is comparable with the
W (c-kit) mutation rather than the SI mutation of mice. This
Genotype
WSlWS
10
+I+
ws/+
WSlWS
50
+I+
Wsl+
WSlWS
No. of
Mast Cellslcm*
368 f 29 (12)
183 2 9 (9)t
8 f 1 (10)t
3 2 6 f 21 (14)
205 f 13 (13)t
10 L 2 (13)t
317 2 8 (6)
167 f 7 (6)t
1 f 1 (6)t
308 f 21 (11)
98 f 7 (8)t
0 (9)t
*Mean f SE; the number of rats is shown in parentheses.
tp < .oi when compared with values of +/+ rats bythet-test.
Fig 3. (A) The spleen of a C3HIHe mouse 6 days after the cyclophosphamide injection and the whole-body irradiation. No bone marrow cells
were injected. Hematoxylin-eosin, original magnification x40. (B) The spleen of a C3H/He mouse 6 days after bone marrow transplantation from
Ws/ Ws rats. Arrows indicate very small foci of erythropoiesis. Hematoxylin-eosin, original magnification x40. (C) The spleen of a C3HlHe mouse
6 days after bone marrow transplantation from +I+ rats. The red pulp is occupied by hematopoietic cells. Faintly stained areas are white pulps.
Hematoxylin-eosin, original magnification x40. (D) A higher magnification of the red pulp shown in (C). Erythroblasts of various differentiation
stages are observed. Hematoxylin-eosin, original magnification x500.
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
NlWA ET AL
1940
Table 5. Development of Mast Cells in the Skin Pieces
of W s l Ws Rats That Had Grafted Under the Kidney Capsule
of Nude Athymic Rats
DOnON
W I W mice
SllSP mice
WslWs rats
Recipients
+I+
Mice
+I+ Mice
Nude rats
Mast Cellslcm Skin'
414 f 18 (10)
3 f 1 (5)
495 f 42 (12)
*Mean f SE; the number of skin grafts is shown in parentheses.
finding was confirmed in the accompanying report by
Tsujimura et al,?"who cloncd thc c-kit gcnc from +I+ and
WslWs rats.
When bone marrow cells of +I+ rats were transplanted
to C3HIHc mice that had reccived thc cyclophosphamide
injection and the wholc-body irradiation, markcd crythropoiesis was observed in thc rcd pulp of the rccipicnts'
spleen. This finding is consistent with the results of Rauchwcrger et al'"." and Himci.'. Rauchwergcr et aIw-'' showcd
that irradiatcd C3H mice arc good rccipicnts of bone
marrow cells from Lcwis rats and that the numbcr of spleen
colonies pcr injccted rat cells was greater in thc spleen of
C3H micc than in the splccn of syngcneic rats. They showed
that all dividing cclls in thc splecn of C3H rccipicnts had rat
karyotype." Himei" used C3HIHc micc that rcccivcd the
cyclophosphamide injection and the wholc-body irradiation
as recipients of bone marrow cclls from Wister rats. He also
showcd that greater than 93% of dividing cells in the
recipicnts' spleen had rat karyotype after transplantation of
10' rat bone marrow cells. Therefore, we consider that
erythroblasts proliferating in the splcen of C3HIHe mice
were of rat origin after thc transplantation of +I+ rat bone
marrow cells. Although we speculatc that the small foci of
erythropoiesis which developcd after thc transplantation of
Wsl Ws bone marrow cells were also of the donor origin, this
must be confirmed in further studies.
Zsebo et all' purified the ligand for the receptor encoded
by the mouse W (c-kit) locus from Buffalo rat liver conditioned medium. The recombinant ligand produced by using
rat cDNA induced formation of hematopoietic cell colonies
by murine bone marrow cells and devclopment of mast cells
in thc skin of SIISl" mice. This findingsuggcststhat the c-kif
receptor system may function across the species. On the
other hand, the present result suggests that thc ligand of the
mouse origin may stimulatc prolifcration and diffcrcntiation of rat hematopoietic cells. Dcspite the poor growth of
Wsl Ws marrow cells, cells derived from the bone marrow of
Fig 4. Differentiation of germ cells in the testis (A) and t h e ovary
rats at 30 days of age. Hematoxylin-eosin, original
magnification (A) x 125, (E) x80.
(E) of Wsl Ws
+I+ rats proliferated and differentiated in the splcen of
C3HIHe mice.
The magnitude of mast cell deficiency in Wsl Ws rats was
comparablc with that of WIW micc and much morc severe
than that of W I W ' mice." Although males and fcmales of
both WIW' and W I W mice arc stcrilc,'.-'somcof thc males
and fcmales of W s l W rats are fcrtilc. There is a possibility
that the receptor encoded by the c-kit gene may not be
essential for the migration and differentiation of gcrm cclls
in rats.
Rats arc thc most commonly used laboratory animals for
the rcsearch of mast cells. Pcritoncal mast cclls of rats arc
easily obtaincd; subpopulations of mast cclls, ic, conncctivc
tissue type and mucosal type, arc wcll charactcrizcd in
rats."'x Bccausc rats arc largcr than micc, somc cxpcrimcnts, cg, induction and rccording of the asthma-like
condition, may be more casily pcrformcd by using rats than
by using micc. Mast-cell-dcficicnt W I W and SIISI" micc
have bccn shown to be vcry useful for understanding thc
physiologic rolcs of mast cells in vivo.'. Therc is a possibility
that WyIWs rats may be more useful than WIW' and SIISI"
mice. Furthcrmorc, WYIWTrats havc two morc advantages
that they do not share with WIW and SIISI" mice: (1) the
anemia of WslWs rats ameliorates after 10 weeks of agc,
and (2) both malc and fcmale WslWs rats are fcrtilc. The
latter situation may make thc efficient production of WslWs
rats possiblc.
REFERENCES
1. Silvers WK: The Coat Colon of Mice. New York. NY,
Springer-Verlag. 1979
2. Russel ES: Hereditary anemias of the mouse: A review for
geneticists. Adv Genet 20357, 1979
3. Kitamura Y, G o S, Hatanaka K Decrease of mast cells in
W / W mice and their increase by bone marrow transplantation.
Blood 52:447,1978
4. Chabot B. Stephenson DA, Chapman VM, Besmer P, Bernstein A: The proto-oncogene c-kif encoding a transmembrane
tyrosine kinase receptor maps to the mouse W locus. Nature
335388. 1988
5. Geissler EN, Ryan MA, Houseman D E The dominant-white
spotting ( W )locus of the mouse encodes the c-kif proto-oncogene.
Cell 55:185, 1988
6. Besmer P, Murphy PC, George PC, Qui F, Bergold PJ,
Lederman L. Snynder HW, Brodeur D, Zuckerman EE. Hardy
WD: A new acute transforming feline retrovirus and relationship
of its oncogene v-kif with the protein kinase gene family. Nature
320415,1986
7. Yarden Y, Kuang WJ. Yang-Feng T,Coussens L, Munemitsu
S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A: Human
proto-oncogene c-kif : A new cell surface receptor tyrosine kinase
for an unidentified ligand. EMBO J 63341. 19x7
8. Qiu F, Ray P. Brown K. Barker PE, Jhanwar S. Ruddle FH,
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
MAST CELL-DEFICIENT RATS
Besmer P: Primary structure of c-kit: Relationship with the
CSF-1/PDGF receptor kinase family-oncogenic activation of v-kit
involves deletion of extracellular domain and C terminus. EMBO J
7:1003,1988
9. Williams DE, Eisenman J, Baird A, Rauch C, Ness'KV,
March CJ,Park LS, Martin U, Mochizuki DY, Boswell HS,
Burgess GS, Cosman D, Lyman SD: Identification of ligand for the
c-kit proto-oncogene. Cell 63:167,1990
10. Flanagan JG, Leder P: The kit ligand: A cell surface
molecule altered in steel mutant fibroblasts. Cell 63:185,1990
11. Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin
FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Murdock DC,
Jacobson FW,Langley KE, Smith KA, Takeishi T, Cattanach BM,
Galli SJ, Suggs SV: Stem cell factor is encoded at the SI locus of the
mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell
63:213,1990
12. Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW,
Wellner D, Leder P, Besmer P: The hematopoietic growth factor
KL is encoded by the SI locus and is the ligand of the c-kit receptor,
the gene product of the Wlocus. Cell 63:225,1990
13. Mayer TC, Green MC: An experimental analysis of the
pigment defect caused by mutation at the W and SI loci in mice.
Dev Biol18:62, 1968
14. Russel ES, Bernstein SE: Proof of whole-cell implantin
therapy of W-series anemia. Arch Biochem Biophys 125594, 1968
15. Nakayama H, Ru XM, Fujita J, Kasugai T, Onoue H, Hirota
S, Kuroda H, Kitamura Y Growth competition between Wmutant
and wild-type cells in mouse aggregation chimeras. Dev Growth
Dif 32:255,1990
16. McCulloch EA, Simonovitch L, Till JE, Russel ES, Bernstein SE: The cellular basis of the genetically determined hemopoietic defect in anemic mice of genotype SIISl". Blood 26:399,1965
17. Kitamura Y, Go S: Decreased production of mast cells in
SIISP anemic mice. Blood 53:492,1979
18. Nakayama H, Kuroda H, Onoue H, Fujita J, Nishimune Y,
Matsumoto K, Nagano T, Suzuki F, Kitamura Y: Studies of SIISP
+ /+ mouse aggregation chimeras. 11. Effect of the steel locus on
spermatogenesis. Development 102:117,1988
19. Kuroda H, Terada N, Nakayama H, Matsumoto K, Kitamura Y Infertility due to growth arrest of ovarian follicles in SIISI'
mice. Dev Biol126:71,1988
20. Kitamura Y: Heterogeneity of mast cells and phenotypic
change between subpopulations. Ann Rev Immunol7:59,1989
21. Snell GD: Histocompatibility of the mouse. 11. Production
and analysis of isogeneic resistant lines. J Natl Cancer Inst 219343,
1958
22. McCulloch EA, Till JE: Repression of colony-forming ability
of C57BL hematopoietic cells transplanted into non-isologous
hosts. J Cell Comp Physiol61:301,1963
-
1941
23. Cudkowicz G: Natural resistance to foreign hemopoietic and
leukemia grafts, in Cudkowicz G, Landy M, Shearer GM (eds):
Natural Resistance Systems Against Foreign Cells, Tumors, and
Microbes. San Diego, CA, Academic, 1978, p 1
24. Lotzova E: Hematopoietic histocompatibility: Genetic and
immunological aspects, in Schwartz LM (ed): Compendium of
Immunology. New York, NY, van Nostrand Reinhold, 1983, p 468
25. Comas FV,Byrd B L Hemopoietic spleen colonies in the rat.
Radiat Res 32355,1987
26. Vacek A, Bartonickova A, Tkadlecek L Age dependence of
the number of the stem cells in haemopoietic tissues of rats. Cell
Tissue Kinet 9:1, 1976
27. Himei S: Capacity of rat hematopoietic cells to form colonies
in mouse spleen. Acta Hematol Jpn 43:71,1980
28. Kitamura Y, Kawata T, Suda 0,Ezumi K Changed differentiation pattern of colony-forming cells in F, hybrid mice suffering
from graft-versus-host disease. Transplantation 10:455,1970
29. Tsujimura T, Hirota S, Nomura S, Niwa Y, Yamazaki M,
Tono T, Morii E, Kim HM, Kondo K, Nishimune Y, Kitamura Y:
Characterization of Ws mutant allele of rats: A 12 base deletion in
tyrosine kinase domain of c-kit gene. Blood 78:1942,1991
30. Rauchwerger JM, Gallagher MT, Trentin JJ: Role of the
hemopoietic inductive microenvironments (HIM) in xenogeneic
bone marrow transplantation. Transplantation 15:610,1973
31. Rauchwerger JM, Gallagher MT, Trentin JJ: "Xenogeneic
resistance" to rat bone marrow transplantation. I. The basic
phenomenon. Proc Soc Exp Biol Med 143:145,1973
32. Go S, Kitamura Y, Nishimura M: Effect of Wand W alleles
on production of tissue mast cells in mice. J Hered 71:41,1980
33. Enerback L Mast cell heterogeneity: The evolution of the
concept of a specific mucosal mast cell, in Befus AD, Bienenstock
J, Denburg JA (eds): Mast Cell Differentiation and Heterogeneity.
New York, NY,Raven, 1986, p 1
34. Haig DM, McKee TA, Jarrett EEE, Woodbury RG, Miller
HRP: Generation of mucosal mast cells is stimulated in vitro by
factors derived from T cells of heminth-infected rats. Nature
300:188,1982
35. Stevens RL, Lee TDG, Seldin DC, Austen KF, Befus D,
Bienenstock J: Intestinal mucosal mast cells from rats infected with
Nipposrrongylus brusiliensis contain protease-resistant chondroitin
sulfate di-B proteoglycans. J Immunol 137:291,1986
36. Befus D, Lee T, Goto T, Goodacre R, Shanahan F, Bienenstock J: Histologic and functional properties of mast cells in rats
and humans, in Befus AD, Bienenstock J, Denburg JA (eds): Mast
Cell Differentiation and Heterogeneity. New York, NY, Raven,
1986, p 205
37. Galli SJ, Kitamura Y: Animal model of human diseases:
Genetically mast cell-deficient W / W and SI/Sld mice. Their value
for the analysis of the role of mast cells in biologic responses in
vivo. Am J Pathol127:191,1987