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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-07-2213.
HEMATOPOIESIS
From the Department of Pathology, Medical
School/Graduate School of Frontier Bioscience, Osaka University,
Yamada-oka, Suita, Japan.
The mi transcription factor (MITF) is a
basic-helix-loop-helix leucine zipper transcription factor and is
encoded by mi locus. The mi/mi mutant mice
showed a significant decrease of skin mast cells in C57BL/6 (B6)
genetic background but not in WB genetic background. Kit ligand (KitL)
is the most important growth factor for development of mast cells, and
the decrease of skin mast cells in B6-mi/mi mice was
attributable to the reduced expression of c-kit receptor
tyrosine kinase (KIT) that is a receptor for KitL. However, the
expression level of KIT in WB-mi/mi mast cells was comparable with that of B6-mi/mi mast cells, suggesting
that a factor compensating the reduced expression of KIT was present in
WB-mi/mi mice. By linkage analysis, such a factor was
mapped on chromosome 10. The mapped position was closely located to the KitL locus. Two alternative spliced forms are known in KitL mRNA: KL-1
and KL-2. Soluble KitL, which is important for development of skin mast
cells, is produced more efficiently from KL-1 mRNA than from KL-2 mRNA.
The KL-1/KL-2 ratio was higher in WB-mi/mi than in
B6-mi/mi mice, suggesting that the larger amount of soluble KitL may compensate for the reduced expression of KIT in
WB-mi/mi mice.
(Blood. 2003;101:1344-1350) The mi locus encodes mi
transcription factor (MITF), which is a member of
basic-helix-loop-helix-leucine zipper protein family of transcription
factors.1 Mutant mice of mi/mi genotype were found among the offspring of an irradiated mouse,2 and the mutant gene was introduced into C57BL/6 (B6) genetic background mice
(B6-mi/mi mice). The number of skin mast cells in
B6-mi/mi mice decreased to one third that of normal (+/+) B6
mice.3,4
We examined the effect of MITF encoded by the mi
mutant allele (mi-MITF) on the expression of various genes
in cultured mast cells (CMCs). CMCs derived from the spleen of
B6-mi/mi mice were deficient in the expression of
c-kit receptor tyrosine kinase (KIT),5,6 mouse
mast cell protease (mMCP)-2,7 -4,8 -5,9 -6,10 -7,11
-9,7 granzyme B (Gr B),12 and tryptophan hydroxylase (TPH) genes.12 The mi-MITF deletes
1 of 4 consecutive arginines in the basic domain.13,14 The
mi-MITF is defective in the DNA binding
ability15 and the nuclear localization
potential16 and does not transactivate mMCP-2, -4, -6, and
-9 genes. Moreover, we found an inhibitory effect of mi-MITF
in the transactivation of KIT, TPH, Gr B, and mMCP-7
genes by comparing the effect of MITF null
mutations.11,17-19 For example, the expression of
mMCP-7 gene was higher in B6-tg/tg CMCs, in which
no MITF was produced, than in B6-mi/mi CMCs, indicating that
the mi-MITF showed an inhibitory effect on the transcription
of mMCP-7 gene.11 MITF binding site was not
present in the promoter region that was essential for transcription of
mMCP-7 gene. In contrast, a c-Jun binding motif was present
in this region, and the binding of c-Jun to the motif was
important for the transactivation. The mi-MITF
inhibited the transactivation ability of c-Jun and suppressed the
expression level of mMCP-7 gene.11
Because the most important growth factor of mast cells is considered to
be Kit ligand (KitL), which is a ligand for KIT,20-23 the
decrease in the skin mast cells may be attributable to the deficient
signal transduction of the KitL-KIT pathway. In fact, the poor
expression of KIT was demonstrated in skin mast cells of
B6-mi/mi mice by immunohistochemistry.24
We attempted to investigate the in vivo biologic features of CMCs
of the mi/mi genotype by transplantation into tissues of mast cell-deficient (WB × C57BL/6) F1
(WBB6F1)-W/Wv mice. To
obtain mi/mi CMCs in the same genetic background of WBB6F1-W/Wv recipients, we
repeatedly backcrossed the mi mutant gene to the WB strain
and obtained WB-mi/mi mice after 8 backcrosses.
Unexpectedly, the number of skin mast cells in WB-mi/mi mice
did not decrease compared with that of WB-+/+ mice, showing that the
effect of mi-MITF on the number of skin mast cells was
influenced by the genetic background. The level of KIT expression was
reduced in WB-mi/mi CMCs, as in the case of
B6-mi/mi CMCs. This suggested that factor(s) compensating
for the reduced expression of KIT was present in WB-mi/mi
mice but not in B6-mi/mi mice. We mapped such a factor on
chromosome 10 using microsatellite markers. The mapped position
was very closely located to the KitL locus, and there is a possibility
that the difference between WB and B6 strains may be attributable to
their different splicing patterns of KitL.
Mice
Staining and counting of mast cells
Cells Pokeweed mitogen-stimulated spleen cell conditioned medium (PWM-SCM) was prepared according to the method described by Nakahata et al.27 Mice at 2 weeks old were used to obtain CMCs. Mice were killed by decapitation after ether anesthesia, and spleens were removed. Spleen cells were cultured in -minimal essential medium
(-MEM) (ICN Biomedicals, Costa Mesa, CA) supplemented with 10%
PWM-SCM and 10% fetal calf serum (FCS) (Nippon Bio-supp Center, Tokyo,
Japan). Half of the medium was replaced every 5 days. More than 95% of
cells contained alcian blue-positive granules and were considered to
be CMCs 4 weeks after initiation of the culture.
Northern blotting Each RNA sample was prepared from 1.0 × 107 CMCs by the lithium chloride-urea method.28 Northern blot analysis was performed using mMCP-2,29 mMCP-4,30 mMCP-5,31 mMCP-6,32 Gr B,12 KIT,33 TPH,12 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)34 cDNAs labeled with-[32P]-deoxycytidine triphosphate
(dCTP; 10 mCi/mL [370 MBq]; DuPont/NEN Research Products,
Boston, MA) by random oligonucleotide priming. After hybridization at
42°C, blots were washed to a final stringency of 0.2 × SSC (1 ×
SSC is 150 mM NaCl and 15 mM trisodium citrate, pH 7.4) and subjected
to autoradiography.
Immunoblotting The whole-cell extracts of B6-+/+, B6-mi/mi, WB-+/+, and WB-mi/mi CMCs were obtained by the method described previously.16 The extract was suspended in loading buffer, boiled, and analyzed by immunoblot with anti-KIT polyclonal antibody (Santa Cruz Biotech, Santa Cruz, CA) and antitubulin antibody (Santa Cruz Biotech).MTT assay To examine the response to recombinant mouse (rm) KitL, an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; Sigma, St Louis, MO) rapid calorimetric assay was carried out. Triplicate aliquots of 3 × 104 CMCs suspended in 100 µL-MEM
supplemented with 10% FCS were cultured in 96-well microtitered plates
for 48 hours at 37°C in the presence or absence of various
concentrations of rmKitL. MTT (10 µL of 5 mg/mL solution of MTT in
phosphate-buffered saline [PBS]) was added to all wells and
incubated for 4 hours at 37°C. Acid 2-propanol was added and mixed
thoroughly to dissolve the dark blue crystals. The optical
density (OD) was then measured on a Micro-enzyme-linked
immunosorbent assay plate reader (Corona Electric, Ibaragi,
Japan) with a test wavelength of 540 nm and a reference wavelength of
620 nm.
Linkage analysis Genomic DNA was obtained from the tail of (F1 × B6)-mi/mi mice by phenol extraction.35 Genotyping for each (F1 × B6)-mi/mi mouse was carried out by polymerase chain reaction (PCR) using genomic DNA as a template, and we determined whether each microsatellite locus was homozygous (B6/B6) or heterozygous (B6/WB). PCR primer sets were purchased from Invitrogen (Carlsbad, CA). Genotyping data on each microsatellite marker were subjected to 2 analysis.
Sequence analysis of the coding region of KitL To examine the sequence of the coding region of KitL, PCR was carried out with Pyrobest Taq DNA polymerase (Takara, Kyoto, Japan). The cDNAs of skin of 3 B6-mi/mi mice and 3 WB-mi/mi mice were used as a template. The primers for PCR were 5'-GCTGCCTGGGCTGGATCGCAGCGCTG and 5'-CTGTTACCAGCCACTGTGCGAAGGTAA. The amplified fragment containing the coding region of KitL was cloned into EcoRV site of pBluescript (Stratagene, La Jolla, CA), and the sequence was analyzed with ABI 3100 sequencer (Applied BioSystems, Foster City, CA). The sequence was verified in both directions.Sequence analysis of introns of KitL gene The introns 5 and 6 of the KitL gene were amplified by long and accurate (LA)-PCR using the genomic DNA obtained from the tail of 2 B6-+/+ mice and 2 WB-+/+ mice. Intron 5 was amplified using the following primers: 5'-TGGTGGCATCTGACACTAGTGA corresponding to the sequence of exon 5 and 5'-GCTACTGCTGTCATTCCTAAGG corresponding to the sequence of exon 6. Intron 6 was amplified using the following primers: 5'-CCAGAGTCAGTGTCACAAAACC corresponding to the sequence of exon 6 and 5'-CTTCCAGTATAAGGCTCCAAAAGC corresponding to the sequence of exon 7. The amplified fragment was cloned into the EcoRV site of pBluescript, and the sequence was analyzed with the ABI 3100 sequencer.Semiquantitative reverse transcription (RT)-PCR analysis Four micrograms of total RNAs was extracted from the dorsal skin of 3 B6-mi/mi and 3 WB-mi/mi mice. The extracted RNAs were subjected to reverse transcription by Superscript (Invitrogen), and the single-strand cDNAs were obtained. One microliter, 0.1 µL, or 0.01 µL of the reaction mixture was added to 25 µL of PCR mixture containing 1.25 units of Taq DNA polymerase (Roche Diagnostics, Mannheim, Germany) and 25 pmol of each of the primers. PCR was carried out to amplify the fragment between exons 7 and 9 of the KitL gene using the primers 5'-AAGACTCGGGCCTACAATGGACAGCCATGG corresponding to the sequence of exon 7 and 5'-CAATGTTGATACGTCCACAATTAC corresponding to the sequence of exon 9.RT-PCR Southern blotting The cDNA used for RT-PCR Southern blotting was obtained as described in "Semiquantitative reverse transcription (RT)-PCR analysis." PCR was carried out to amplify the fragment between exons 5 and 7 of the KitL gene using the primers 5'-TGGTGGCATCTGACACTAGTGA corresponding to the sequence of exon 5 and 5'-CTTCCAGTATAAGGCTCCAAAAGC corresponding to the sequence of exon 7. Fifteen cycles of PCR were performed, and the resulting amplified fragment was electrophoresed in 4% agarose gel. The blotted membrane was hybridized at 67°C with-[32P]-labeled KitL
fragment corresponding to the sequence between exons 5 and 7.
RNase protection assay The pBluescript containing the coding region of KitL was linearized by SpeI. The-[32P]-labeled
antisense riboprobe was synthesized from the linearized plasmid using
T3 RNA polymerase (Invitrogen). RNase protection assay was carried out
with an RPA III Kit (Ambion, Austin, TX) according to the
manufacturer's instructions. The intensity of the protected band for
KL-1 mRNA and that of KL-2 mRNA was quantified using NIH Image
(http://rsb.info.nih.gov/nih-image/).
The appearance of WB-mi/mi mice was comparable with
that of B6-mi/mi mice: white coat color, microphthalmia, and
failure of eruption of incisors. On the other hand, the appearance of
WB-mi/+ mice was different from that of B6-mi/+
mice (Figure 1). Abdominal white patches
lacking melanocytes were larger in WB-mi/+ mice than in
B6-mi/+ mice (Figure 1).
The number of skin mast cells of B6-mi/mi mice decreased to
one third that of B6-+/+ mice, but that of WB-mi/mi mice was
comparable with that of WB-+/+ mice (Table
1). The number of skin mast cells was
significantly higher in WB-+/+ mice than in B6-+/+ mice (Table 1). As a
result, the number of skin mast cells observed in WB-mi/mi mice was higher than the number in B6-+/+ mice, showing the critical effect of genetic backgrounds on the number of skin mast cells.
The expression of genes whose transcription had been shown to be
deficient in B6-mi/mi CMCs was compared between
WB-mi/mi CMCs and WB-+/+ CMCs by Northern blotting (Figure
2). The examined genes were divided into
2 groups: genes showing the normal expression in WB-mi/mi
CMCs and genes showing the deficient expression in WB-mi/mi
CMCs, as in the case of B6-mi/mi CMCs. The mMCP-2,
mMCP-4, mMCP-5, and Gr B genes belonged to the former
group, and the mMCP-6, KIT, and TPH genes
belonged to the latter group (Figure 2).
Immunoblot demonstrated that the amount of KIT protein was reduced in
WB-mi/mi CMCs, and its level was comparable with that of
B6-mi/mi CMCs (Figure 3A).
When examined with MTT assay, the response to rmKitL was comparable
between WB-mi/mi CMCs and B6-mi/mi CMCs (Figure
3B).
It was possible that the decrease of skin mast cells in mice of mi/mi genotype might be attributable to the reduced expression of KIT.4 However, the number of skin mast cells was normal despite the reduced expression of KIT in WB-mi/mi mice. This suggested that factor(s) compensating for the reduced expression of KIT may be present in WB-mi/mi mice but not in B6-mi/mi mice. We examined the number of skin mast cells in
WBB6F1-mi/mi mice. The number of skin mast cells
did not decrease in WBB6F1-mi/mi mice compared
with that of WBB6F1-+/+ mice, suggesting that the nonreduction of skin mast cells observed in WB-mi/mi mice
was inherited dominantly (Table 1). Next,
WBB6F1-mi/+ mice were backcrossed to
B6-mi/+ mice, and (F1 × B6)-mi/mi mice were obtained. The number of skin mast cells
in (F1 × B6)-mi/mi mice was bimodal
(Figure 4). Of 131 (F1 × B6)-mi/mi mice, 73 mice showed the high number of skin
mast cells (more than 140 per cm skin) that was comparable with the
value observed in WB-mi/mi mice, whereas 58 mice showed the
low number of skin mast cells (fewer than 100 per cm skin) that was
comparable with the value observed in B6-mi/mi mice. We
calculated the ratio of mice with the high number of mast cells to mice
with the low number of mast cells and examined whether the ratio fitted
with the ratio predicted for a single-dominant inheritance. The
observed ratio fitted well with the predicted ratio (
The expression levels of mMCP-2, mMCP-4, and mMCP-5
genes did not decrease in WB-mi/mi CMCs (Figure 2). We
examined whether the factor that maintained the skin mast cell number
in WB-mi/mi mice correlated with the high expression levels
of mMCP-2, mMCP-4, and mMCP-5 genes. We obtained
CMCs from 4 (F1 × B6)-mi/mi mice with
high numbers of skin mast cells and 4 (F1 × B6)-mi/mi mice with low numbers of skin mast cells. One of
4 (F1 × B6)-mi/mi mice with high numbers
of skin mast cells showed high expression levels of mMCP-2,
mMCP-4, and mMCP-5 genes, but the other 3 mice showed
low expression levels (Figure 5). Two of
4 (F1 × B6)-mi/mi mice with low numbers
of skin mast cells showed high expression levels of mMCP-2,
mMCP-4, and mMCP-5 genes, but the other 2 mice showed
low expression levels (Figure 5). The numbers of skin mast cells in
(F1 × B6)-mi/mi mice did not correlate
with the expression levels of mMCP-2, mMCP-4, and
mMCP-5 genes.
Linkage analysis was carried out using the aforementioned 131 (F1 × B6)-mi/mi mice to map the locus
encoding the factor compensating for the reduced expression level of
KIT. We selected 70 microsatellite loci that showed apparent
differences between B6 and WB strains. The (F1 × B6)-mi/mi mice were typed to be homozygous (B6/B6) or heterozygous (B6/WB) for each microsatellite locus. The ratio of B6/B6
to B6/WB mice was subjected to
Among the loci reported around the position with the highest
We examined the expression level of KitL mRNA in skin tissues of
B6-mi/mi and WB-mi/mi mice by semiquantitative
RT-PCR. The expression level was comparable between B6-mi/mi
and WB-mi/mi mice (Figure 9A).
Two isoforms of KitL are known: KL-1 and KL-2.36,37 KL-1
but not KL-2 contains the fragment derived from exon 6 of KitL
gene.36,37 Because Besmer and his colleagues reported that
KL-1 but not KL-2 was important for development of the skin mast
cells,38 we examined the ratio of KL-1 mRNA to KL-2 mRNA (KL-1/KL-2 ratio) in skin tissues. To distinguish KL-1 from KL-2, primers encompassing exon 6 were used in the RT-PCR Southern analysis. The intensity of the band for KL-1 mRNA was comparable with that of
KL-2 mRNA in the skin tissues of B6-mi/mi mice (Figure 9B). In contrast, the intensity of the band for KL-1 mRNA was larger than
that of KL-2 mRNA in the skin tissue of WB-mi/mi mice
(Figure 9A). The KL-1/KL-2 ratio was approximately 3-fold higher in the skin of WB-mi/mi mice than in the skin of
B6-mi/mi mice (Figure 9C). Similar results were obtained
when the KL-1/KL-2 ratio was compared between B6-+/+ and WB-+/+ mice
(data not shown).
The KL-1/KL-2 ratio was also evaluated using RNase protection assay.
The KL-1/KL-2 ratio was higher in the skin of WB-mi/mi mice
than in the skin of B6-mi/mi mice (Table
2).
The B6-mi/mi mice are the most widely used homozygous mutant of mi locus, and the decrease of mast cells in the skin tissue of B6-mi/mi mice was first described by Stechschulte et al.3 Because the skin is the easiest tissue to examine the number of mast cells, mice of the mi/mi genotype have been considered to be a mutant with mast cell deficiency. However, the present result showed that the genetic background influenced the number of mast cells in mice of the mi/mi genotype. When compared with the wild-type (+/+) mice of the same genetic background, the number of skin mast cells decreased significantly in B6-mi/mi mice but not in WB-mi/mi mice. This is consistent with the old result of Stevens and Loutit.39 They reported that the number of skin mast cells did not decrease in G-mi/mi and (G × CBA) F1-mi/mi mice. The tissues examined also influenced the comparative numbers of mast cells. In contrast to skin tissue, mast cells did decrease in the gastrointestinal canal and spleen of G-mi/mi and (G × CBA) F1-mi/mi mice.39 Stechschulte et al3 also reported the marked decrease of mast cells in the peritoneal cavity of B6-mi/mi mice. These results were consistent with our unpublished result that practically no mast cells were detectable in the gastrointestinal canal, spleen, and peritoneal cavity of both WB-mi/mi mice and B6-mi/mi mice (T.J. et al, unpublished data, 2002). Mast cell numbers in tissues other than skin did not appear to be influenced by the genetic backgrounds of mi/mi mice. The WB strain was originally produced by Russell et al to prolong the longevity of the mice with the W/W genotype.40,41 In the cross of B6-W/+ males and females, only 4%, rather than the expected 25%, of W/W individuals were born alive, and the average survival period was 2 days.40 In contrast, when WB-W/+ mice were crossed together, a full 25% live-born W/W offspring was obtained, and the average survival period was 10 days.40 This suggested that factor(s) compensating the W/W mutant genotype was present in WB strain. Now the mutant W allele is known to encode KIT without the extracellular domain.42 This was consistent with the present study that the factor compensating the reduced expression of KIT in mice with the mi/mi genotype was present in WB strain but not in B6 strain. By linkage analysis, the factor compensating the reduced expression of KIT was mapped near the KitL locus on chromosome 10. There is a possibility that KitL itself is the factor. Between the B6 and WB strains, an amino acid alteration was detected at codon 207 of KitL: alanine in the B6 strain and serine in the WB strain. However, this alteration may not be important, because codon 207 varies among species: serine in rats,43 pigs,44 cows,45 and dogs46; proline in human beings47 and cats48; and aspargine in chicken.49 Besides the alteration in the coding region, the ratio of alternatively spliced KitL mRNAs (KL-1/KL-2 ratio) was different between B6 and WB strains. There are 2 isoforms of KitL protein: membrane-bound form and soluble form.36,37 The latter is produced by proteolytic cleavage from the former. Because the protein translated from KL-2 mRNA lacks the major proteolytic cleavage site, soluble KitL is produced more efficiently from KL-1 mRNA than from KL-2 mRNA. The KL-1/KL-2 ratio was higher in the WB strain than in the B6 strain. The production level of soluble KitL might be higher in the WB strain than in the B6 strain. In fact, the number of skin mast cells was significantly higher in WB-+/+ mice than in B6-+/+ mice. The number of skin mast cells decreased in the KL-2 gene knock-in mice, in which no KL-1 is produced.38 The number of skin mast cells increased in the transgenic mice of the KL-1 gene but not in the transgenic mice of the KL-2 gene.50 These results suggested that the soluble KitL is critical for the production of normal numbers of skin mast cells. The development of melanocytes depends on MITF.51 The abdominal white patches lacking melanocytes were larger in WB-mi/+ mice than in B6-mi/+ mice, suggesting that melanocyte progenitors may migrate more easily in the skin of B6-mi/+ mice than in the skin of WB-mi/+ mice. Kunisada et al reported that the increase of melanocytes was observed more markedly in transgenic mice of the KL-2 gene than in transgenic mice of the KL-1 gene.50 This suggested that, in contrast to development of mast cells in the skin, membrane-bound KitL might be more important for the development of melanocytes than soluble KitL. Because the KL-1/KL-2 ratio was lower in B6 strain than in the WB strain, the skin of B6-mi/+ mice may be more suitable for the development of melanocytes than the skin of WB-mi/+ mice. There is another possibility that the factor compensating for the reduced expression of KIT is not related to KitL. Rhim et al mapped a modifier gene of endothelin receptor B gene near the KitL locus.52 Homozygous mice with mutant endothelin receptor B gene (Ednrbs/Ednrbs mice) show abnormal pigmentation patterns. The genetic background of the mutants affected the pigmentation pattern. C3H-Ednrbs/Ednrbs mice have white patches on the forehead and abdomen, whereas Mayer-Ednrbs/Ednrbs mice have white patches on the back and abdomen. Although the pigmentation patterns of Ednrbs/Ednrbs mice are influenced by multiple modifier genes, one of them was mapped near the KitL locus. This modifier gene of the Ednrb locus may be consistent with the locus mapped in the present study. On the other hand, either the mutation of Ednrb gene or that of MITF gene causes a similar abnormality (Waardenburg syndrome 453 and Waardenburg syndrome 2, respectively54). The modifier gene of endothelin receptor B and that of KIT might be common. Taken together, the mutation compensating for the reduced expression of KIT in WB-mi/mi mice was mapped at the position very closely located to the KitL locus. Although the different splicing pattern of KitL between the B6 and WB strains was a plausible explanation, more analysis will be needed to identify such a mutation.
The authors thank Dr H. Hiai for helpful discussions and Ms C. Murakami and Ms T. Sawamura for technical assistance.
Submitted July 23, 2002; accepted September 30, 2002.
Prepublished online as Blood First Edition Paper, October 17, 2002; DOI 10.1182/blood-2002-07-2213.
Supported by grants from the Ministry of Education, Culture, Sports, Science and Technology and from Senri Life Science Foundation.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Yukihiko Kitamura, Department of Pathology, Rm C2, Osaka University Medical School, Yamada-oka 2-2, Suita, 565-0871, Japan; e-mail: kitamura{at}patho.med.osaka-u.ac.jp.
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Abstract
Introduction
D10Mit12 and
D10Mit96
450 to 