Abstract
Desmosomal cadherins are essential cell adhesion molecules expressed in the epidermis. We identified a mutation of a cadherin superfamily member, namely, desmoglein 4 (Dsg4), in early onset of death (EOD)hage mice with hypotrichosis. The mutation was induced by the insertion of an early transposon II-β into intron 8 of Dsg4. Mast cell hyperplasia was observed in the skin of EODhage mice. The abnormally expanded population of lpr T cells, i.e., CD4−CD8−B220+Thy1.2+ αβT cells, in the splenocytes of EOD mice was reduced in EODhage mice. Therefore, it was suspected that the long-living mutant EODhage mice were selected from lupus-prone EOD mice because of their immunological immaturity. These findings clearly indicate that Dsg4 is an important molecule for the formation of hair follicles and hypothesize that unorganized hyperplastic hair follicles in anagen due to the Dsg4 mutation provide niches for mast cell precursors in the skin.
Similar content being viewed by others
References
Abraham SN, Malaviya R (1997) Mast cells in infection and immunity. Infect Immun 65:3501–3508
Adachi M, Watanabe-Fukunaga R, Nagata S (1993) Aberrant transcription caused by the insertion of an early transposable element in an intron of the Fas antigen gene of lpr mice. Proc Natl Acad Sci U S A 90:1756–1760 doi:10.1073/pnas.90.5.1756
Arck PC, Handjiski B, Peters EM, Peter AS, Hagen E, Fischer A et al (2003) Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways. Am J Pathol 162:803–814
Baust C, Baillie GJ, Mager DL (2002) Insertional polymorphisms of ETn retrotransposons include a disruption of the wiz gene in C57BL/6 mice. Mamm Genome 13:423–428 doi:10.1007/s00335-002-2178-3
Baust C, Gagnier L, Baillie GJ, Harris MJ, Juriloff DM, Mager DL (2003) Structure and expression of mobile ETnII retroelements and their coding-competent MusD relatives in the mouse insertional polymorphisms of ETn retrotransposons include a disruption of the wiz gene in C57BL/6 mice. J Virol 77:11448–11458 doi:10.1128/JVI.77.21.11448-11458.2003
Bazzi H, Martinez-Mir A, Kljuic A, Christiano AM (2005) Desmoglein 4 mutations underlie localized autosomal recessive hypotrichosis in humans, mice, and rats. J Investig Dermatol Symp Proc 10:222–224 doi:10.1111/j.1087-0024.2005.10110.x
Bischoff SC, Sellge G (2002) Mast cell hyperplasia: role of cytokines. Int Arch Allergy Immunol 127:118–122 doi:10.1159/000048181
Fagotto F, Gumbiner BM (1996) Cell contact-dependent signaling. Dev Biol 180:445–454 doi:10.1006/dbio.1996.0318
Garrod D, Chidgey M (2007) Desmosome structure, composition and function. Biochim Biophys Acta 9:9
Hofmann M, Harris M, Juriloff D, Boehm T (1998) Spontaneous mutations in SELH/Bc mice due to insertions of early transposons: molecular characterization of null alleles at the nude and albino loci. Genomics 52:107–109 doi:10.1006/geno.1998.5409
Honda S, Nemoto K, Mae T, Kinjoh K, Kyogoku M, Kawamura H et al (1999) Mice with early onset of death (EOD) due to lupus glomerulonephritis. Clin Exp Immunol 116:153–163 doi:10.1046/j.1365-2249.1999.00847.x
Huntley JF, Newlands GF, Gibson S, Ferguson A, Miller HR (1985) Histochemical demonstration of chymotrypsin like serine esterases in mucosal mast cells in four species including man. J Clin Pathol 38:375–384 doi:10.1136/jcp.38.4.375
Jahoda CA, Kljuic A, O’Shaughnessy R, Crossley N, Whitehouse CJ, Robinson M et al (2004) The lanceolate hair rat phenotype results from a missense mutation in a calcium coordinating site of the desmoglein 4 gene. Genomics 83:747–756 doi:10.1016/j.ygeno.2003.11.015
Kljuic A, Bazzi H, Sundberg JP, Martinez-Mir A, O'Shaughnessy R, Mahoney MG et al (2003) Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris. Cell 113:249–260 doi:10.1016/S0092-8674(03)00273-3
Komori H, Furukawa H, Mori S, Ito MR, Terada M, Zhang MC et al (2006) A signal adaptor SLAM-associated protein regulates spontaneous autoimmunity and Fas-dependent lymphoproliferation in MRL-Faslpr lupus mice. J Immunol 176:395–400
Kumamoto T, Shalhevet D, Matsue H, Mummert ME, Ward BR, Jester JV et al (2003) Hair follicles serve as local reservoirs of skin mast cell precursors. Blood 102:1654–1660 doi:10.1182/blood-2003-02-0449
Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002 doi:10.1038/nature05010
McGrath JA, Wessagowit V (2005) Human hair abnormalities resulting from inherited desmosome gene mutations. Keio J Med 54:72–79 doi:10.2302/kjm.54.72
Messenger AG, Bazzi H, Parslew R, Shapiro L, Christiano AM (2005) A missense mutation in the cadherin interaction site of the desmoglein 4 gene underlies localized autosomal recessive hypotrichosis. J Invest Dermatol 125:1077–1079 doi:10.1111/j.0022-202X.2005.23903.x
Meyer B, Bazzi H, Zidek V, Musilova A, Pravenec M, Kurtz TW et al (2004) A spontaneous mutation in the desmoglein 4 gene underlies hypotrichosis in a new lanceolate hair rat model. Differentiation 72:541–547 doi:10.1111/j.1432-0436.2004.07209007.x
Noli C, Miolo A (2001) The mast cell in wound healing. Vet Dermatol 12:303–313 doi:10.1046/j.0959-4493.2001.00272.x
Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S (2006) Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312:1669–1672 doi:10.1126/science.1124978
Schweizer J (2006) More than one gene involved in monilethrix: intracellular but also extracellular players. J Invest Dermatol 126:1216–1219 doi:10.1038/sj.jid.5700266
Wang HW, Tedla N, Hunt JE, Wakefield D, McNeil HP (2005) Mast cell accumulation and cytokine expression in the tight skin mouse model of scleroderma. Exp Dermatol 14:295–302 doi:10.1111/j.0906-6705.2005.00315.x
Weller K, Foitzik K, Paus R, Syska W, Maurer M (2006) Mast cells are required for normal healing of skin wounds in mice. FASEB J 20:2366–2368 doi:10.1096/fj.06-5837fje
Whittock NV (2003) Genomic sequence analysis of the mouse desmoglein cluster reveals evidence for six distinct genes: characterization of mouse DSG4, DSG5, and DSG6. J Invest Dermatol 120:970–980 doi:10.1046/j.1523-1747.2003.12257.x
Yoshida M, Saiga K, Hato T, Iwaki S, Niiya T, Arita N et al (2006) Cappuccino mutation in an autoimmune-prone strain of mice suggests a role of platelet function in the progression of immune complex crescentic glomerulonephritis. Arthritis Rheum 54:2934–2943 doi:10.1002/art.22059
Acknowledgements
The authors thank Dr. Toshihiko Shiroishi (National Institute of Genetics) for providing MSM mice, Mr. Takuo Hiwatari (Nippon Kayaku Co., Ltd.) and Mr. Kazuumi Kotake (Nippon Kayaku Co., Ltd.) for providing technical assistance in animal experiments, Ms. Naomi Yamaki (Tohoku University) for providing technical assistance in histology, and Ms. Noriko Fujisawa (Tohoku University) and Ms. Emi Yura (Tohoku University) for secretarial assistance. This study is supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan to H.F. (# 16790221) and M.O. (# 16390113, 19390108, and 19659096). The authors declare that the experiments comply with the current laws of Japan.
Author information
Authors and Affiliations
Corresponding author
Additional information
DDBJ accession numbers of the sequences in this article: AB240191, AB240192
MGI accession number of the mutant allele in this article: MGI:3766998
Rights and permissions
About this article
Cite this article
Zhang, MC., Furukawa, H., Tokunaka, K. et al. Mast cell hyperplasia in the skin of Dsg4-deficient hypotrichosis mice, which are long-living mutants of lupus-prone mice. Immunogenetics 60, 599–607 (2008). https://doi.org/10.1007/s00251-008-0320-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-008-0320-4