腹侧黄色被毛小鼠的生物学特性及突变基因的染色体定位
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摘要
腹侧黄色被毛小鼠是中国科学院上海实验动物中心工作人员在小鼠正常生产繁殖过程中发现的一种突变种小鼠,其遗传背景为C57BL/6J(简称B6),最显著的可见表型为头颈躯干腹侧面(从下颌至肛门)被覆黄色被毛,腹侧与背侧交界线清楚。本实验对腹侧黄色被毛小鼠的生物学特性进行了研究,并对突变基因进行了染色体定位。具体研究内容分为以下两部分:
1腹侧黄色被毛小鼠的生物学特性
本实验所研究的腹侧黄色被毛小鼠来源于自发性突变,经遗传试验证实该突变符合单基因显性遗传的模式。组织病理学及组织化学研究发现腹侧黄色被毛小鼠腹部表皮黑色素细胞数目及毛囊内黑色素较其背景品系B6少,而背部与B6无明显差别;黄色被毛小鼠毛发直接镜检,可见腹部毛发的颜色较B6浅,结构正常,背部与B6无明显差别;腹侧黄色被毛小鼠肾脏脏器系数较正常B6小鼠大,差异呈极显著性(P<0.01);突变小鼠的血糖值,雄性为7.64±0.820mmol/L,雌性为7.46±0.992mmol/L,而背景品系的雄性为2.14±0.532mmol/L,雌性为2.59±0.896mmol/L,两者间差异呈极显著性,其余指标包括体重、各重要脏器病理切片及血液生理学未发现明显异常,尽管我们尚未确定这些变化之间的内部联系,但腹侧黄色被毛小鼠由于具有高血糖的特征,有可能被开发成为一个新型的糖尿病模型。到目前为止,腹侧黄色被毛小鼠的模型特征与对应的人类疾病尚未明确,但这些生物学数据将为突变基因的鉴定提供非常有用的线索。
2黄色被毛小鼠突变基因的染色体定位
通过文献查阅,参考前人的研究结果,本实验首先选取用于对突变基因进行初步定位的39个微卫星标记,这些标记基本平均分布于小鼠基因组,在B6及D2小鼠之间呈多态性且差异至少在4bp以上。同时,大量繁殖F2代小鼠并且优先从第2、8号染色体开始对样本进行PCR扩增,在对扩增结果逐一连锁分析后,将突变基因定位于第2号染色体上。然后,我们在靠近突变基因的附近选取新的微卫星标记,通过这些微卫星标记将突变基因所在区域进一步减小到D2Mit307和D2Mit310之间约2.7 cM的范围内,在确定小鼠基因数据库中已没有合适的微卫星位点可供使用之后,我们开始选择SNP标记,这些标记必须在B6小鼠及D2小鼠间有碱基多态性,这种多态性能够通过对PCR产物的测序进行区分。在本实验中我们共使用了11个微卫星标记和3个SNP标记,最终通过对196只F2小鼠的连锁分析,将腹侧黄色被毛小鼠的突变基因定位于第2号染色体距着丝粒149804749bp到155060764bp内大约5.3Mb之内,为进一步克隆鉴定突变基因奠定了基础。
The venter-yellow pigmentation mouse arose spontaneously in the C57BL/6J inbred strain mouse which was found by the staff of Shanghai Laboratory Animal Center, Chinese Academy of Science. It presented a special phenotype with yellow coat on the ventral surface of head, neck and trunk (from the lower jaw to the anus) and a clear boundary between ventral side and dorsal side. This thesis about the mutant mouse includes the following two parts:Investigating the biocharacteristics and mapping mutant gene of the venter-yellow pigmentation mouse.
1. The biocharacteristics of the venter-yellow pigmentation mouse
The mutation of venter-yellow pigmentation mouse was spontaneous and the mutant allele was inherited as single-gene dominant inheritance confirmed by genetic experiment. Compared with B6 through histopathologic and histochemical study, the mutant mouse was found that the number of melanocytes in epidermis and melanin in hair follicle of the abdominal skin were less than that of its background strain while there was no significant difference between the dorsal skin of the two strains; observed directly under microscopy, the ventral hair color of mutant mouse was lighter than that of wild type mouse while its structure was normal. There was no big difference in the color and structure of dorsal hair. The venter-yellow pigmentation mice had bigger kidney than B6 and statistical analysis showed this difference was highly significant (P<0.01). The serum glucose level of the mutant mouse in the male and the female were 7.64±0.820mmol/L and 7.46±0.992mmol/L while in the male and the female of B6 were 2.14±0.532mmol/L and 2.59±0.896mmol/L respectively, and the difference was also with high statistical significance (P<0.01). There were no significant differences between venter-yellow pigmentation mouse and B6 in other biological parameters such as weight, pathological sections of major organs and blood physiology. Although we have not understood the potential relationships of these changes, the high serum glucose level implies that the venter-yellow pigmentation mouse might be used as a new diabetes animal model. Also, before the human homologous disease corresponding to the venter-yellow pigmentation mouse is confirmed, these biological data of the venter-yellow pigmentation mouse will offer very useful clues to subsequent identification of mutant gene.
2. Mapping the mutant gene of venter-yellow pigmentation mouse
On the basis of many materials and former achievements referenced, 39 microsatellites, which distributed equally on 19 euchromosomes of mouse with at least 4bp differences of polymorphism between B6 and DBA (D2), was prepared for genome-wide scan. Meanwhile, [B6D2F1×D2] F2 mice for mapping mutant gene were bred and 48 genomic DNA samples were preferentially scanned with microsatellites on chromosome 2 and 8. After each of the samples was amplified by primers of these microsatellites, we evaluated amplification results using linkage-analysis method, and the mutant gene was located on chromosome 2 near by D2Mit229. Consequently, the scope of mutant gene was narrowed step by step by selected microsatellite marks approaching the mutant gene. After the mutant gene was narrowed dawn to about 2.7 cM between D2Mit307 and D2Mit310, there was no suitable microsatellite to choose in Mouse Genomic Informatics ( MGI ) database , a new type maker named single-nucleotide polymorphism(SNP) was used which should show the difference of single base polymorphism between B6 and D2 by sequencing the PCR products. In this research, 11 microsatellite marks and 3 SNP marks were used to amplify 196 F2 mice and the mutant gene was narrowed down to 5.3Mb region between rs13476833 and rs27310903 on chromosome 2. Preliminary results of phenotype analysis and gene location provide a solid basis for further identification of mutant gene.
1腹侧黄色被毛小鼠的生物学特性
本实验所研究的腹侧黄色被毛小鼠来源于自发性突变,经遗传试验证实该突变符合单基因显性遗传的模式。组织病理学及组织化学研究发现腹侧黄色被毛小鼠腹部表皮黑色素细胞数目及毛囊内黑色素较其背景品系B6少,而背部与B6无明显差别;黄色被毛小鼠毛发直接镜检,可见腹部毛发的颜色较B6浅,结构正常,背部与B6无明显差别;腹侧黄色被毛小鼠肾脏脏器系数较正常B6小鼠大,差异呈极显著性(P<0.01);突变小鼠的血糖值,雄性为7.64±0.820mmol/L,雌性为7.46±0.992mmol/L,而背景品系的雄性为2.14±0.532mmol/L,雌性为2.59±0.896mmol/L,两者间差异呈极显著性,其余指标包括体重、各重要脏器病理切片及血液生理学未发现明显异常,尽管我们尚未确定这些变化之间的内部联系,但腹侧黄色被毛小鼠由于具有高血糖的特征,有可能被开发成为一个新型的糖尿病模型。到目前为止,腹侧黄色被毛小鼠的模型特征与对应的人类疾病尚未明确,但这些生物学数据将为突变基因的鉴定提供非常有用的线索。
2黄色被毛小鼠突变基因的染色体定位
通过文献查阅,参考前人的研究结果,本实验首先选取用于对突变基因进行初步定位的39个微卫星标记,这些标记基本平均分布于小鼠基因组,在B6及D2小鼠之间呈多态性且差异至少在4bp以上。同时,大量繁殖F2代小鼠并且优先从第2、8号染色体开始对样本进行PCR扩增,在对扩增结果逐一连锁分析后,将突变基因定位于第2号染色体上。然后,我们在靠近突变基因的附近选取新的微卫星标记,通过这些微卫星标记将突变基因所在区域进一步减小到D2Mit307和D2Mit310之间约2.7 cM的范围内,在确定小鼠基因数据库中已没有合适的微卫星位点可供使用之后,我们开始选择SNP标记,这些标记必须在B6小鼠及D2小鼠间有碱基多态性,这种多态性能够通过对PCR产物的测序进行区分。在本实验中我们共使用了11个微卫星标记和3个SNP标记,最终通过对196只F2小鼠的连锁分析,将腹侧黄色被毛小鼠的突变基因定位于第2号染色体距着丝粒149804749bp到155060764bp内大约5.3Mb之内,为进一步克隆鉴定突变基因奠定了基础。
The venter-yellow pigmentation mouse arose spontaneously in the C57BL/6J inbred strain mouse which was found by the staff of Shanghai Laboratory Animal Center, Chinese Academy of Science. It presented a special phenotype with yellow coat on the ventral surface of head, neck and trunk (from the lower jaw to the anus) and a clear boundary between ventral side and dorsal side. This thesis about the mutant mouse includes the following two parts:Investigating the biocharacteristics and mapping mutant gene of the venter-yellow pigmentation mouse.
1. The biocharacteristics of the venter-yellow pigmentation mouse
The mutation of venter-yellow pigmentation mouse was spontaneous and the mutant allele was inherited as single-gene dominant inheritance confirmed by genetic experiment. Compared with B6 through histopathologic and histochemical study, the mutant mouse was found that the number of melanocytes in epidermis and melanin in hair follicle of the abdominal skin were less than that of its background strain while there was no significant difference between the dorsal skin of the two strains; observed directly under microscopy, the ventral hair color of mutant mouse was lighter than that of wild type mouse while its structure was normal. There was no big difference in the color and structure of dorsal hair. The venter-yellow pigmentation mice had bigger kidney than B6 and statistical analysis showed this difference was highly significant (P<0.01). The serum glucose level of the mutant mouse in the male and the female were 7.64±0.820mmol/L and 7.46±0.992mmol/L while in the male and the female of B6 were 2.14±0.532mmol/L and 2.59±0.896mmol/L respectively, and the difference was also with high statistical significance (P<0.01). There were no significant differences between venter-yellow pigmentation mouse and B6 in other biological parameters such as weight, pathological sections of major organs and blood physiology. Although we have not understood the potential relationships of these changes, the high serum glucose level implies that the venter-yellow pigmentation mouse might be used as a new diabetes animal model. Also, before the human homologous disease corresponding to the venter-yellow pigmentation mouse is confirmed, these biological data of the venter-yellow pigmentation mouse will offer very useful clues to subsequent identification of mutant gene.
2. Mapping the mutant gene of venter-yellow pigmentation mouse
On the basis of many materials and former achievements referenced, 39 microsatellites, which distributed equally on 19 euchromosomes of mouse with at least 4bp differences of polymorphism between B6 and DBA (D2), was prepared for genome-wide scan. Meanwhile, [B6D2F1×D2] F2 mice for mapping mutant gene were bred and 48 genomic DNA samples were preferentially scanned with microsatellites on chromosome 2 and 8. After each of the samples was amplified by primers of these microsatellites, we evaluated amplification results using linkage-analysis method, and the mutant gene was located on chromosome 2 near by D2Mit229. Consequently, the scope of mutant gene was narrowed step by step by selected microsatellite marks approaching the mutant gene. After the mutant gene was narrowed dawn to about 2.7 cM between D2Mit307 and D2Mit310, there was no suitable microsatellite to choose in Mouse Genomic Informatics ( MGI ) database , a new type maker named single-nucleotide polymorphism(SNP) was used which should show the difference of single base polymorphism between B6 and D2 by sequencing the PCR products. In this research, 11 microsatellite marks and 3 SNP marks were used to amplify 196 F2 mice and the mutant gene was narrowed down to 5.3Mb region between rs13476833 and rs27310903 on chromosome 2. Preliminary results of phenotype analysis and gene location provide a solid basis for further identification of mutant gene.
引文
[1]Luo R, Gao J, Wehrle Haller B, et al. Molecular identification of distinct neurogenic and melanogenic neural crest sublineages. Development, 2003, 130(2):321-330.
[2]Kunisada T, Yoshida H, Yamazaki H, et al. Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors. Development, 1998, 125(15):2915-2923.
[3]Nakamura M, Tobin DJ, Richards-Smith B, et al. Mutant laboratory mice with abnormalities in pigmentation: Annotated tables. J Dermatol Sci, 2002, 28:1–33.
[4]Slominski A, Wortsman J, Plonka PM, et al. Hair follicle pigmentation. J Invest Dermatol, 2005, 124:13-21.
[5]Raposo G, Marks MS. Melanosomes--dark organelles enlighten endosomal membranetransport. Nat Rev Mol Cell Biol, 2007, 8:786–97.
[6]Hornyak TJ. The developmental biology of melanocytes and its application to understanding human congenital disorders of pigmentation. Adv Dermatol, 2006, 22: 201–218.
[7]Price ER, Fischer DE. Sensorineural deafness and pigmentation genes: melanocytes and the Mitf transcriptional network. Neuron, 2001, 30: 15–18.
[8]Levy C, Khaled M, Fischer DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med, 2006, 12: 406–414.
[9]Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature, 2007, 445: 843–850.
[10]Passeron T, Valencia JC, Bertolotto C, et al. SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation. Proc Natl Acad Sci U S A, 2007, 104:13984–9.
[11]Yamaguchi Y, Hearing VJ, Itami S, et al. Mesenchymal-epithelial interactions in the skin: aiming for site-specific tissue regeneration. J Dermatol Sci, 2005, 40:1–9.
[12]Yoshida H, Kunisada T, Grimm T, et al. Review:melanocyte migration and survival controlled by SCF/c-kit expression. J Invest Dermatol Symp Proc, 2001, 6(1):1-5.
[13]Kunisada T, Lu SZ, Yoshida H, et al. Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor. J Exp Med, 1998, 187(10):1565-1573.
[14]Kawaguchi Y, Mori N, Nakayama A. Kit ( + ) melanocytes seem to contribute to melanocyte proliferation after UV exposure as precursor cells. J Invest Dermatol, 2001, 116 :920– 925.
[15]Kimura S, Kawakami T, Kawa Y, et al. Bcl-2 reduced and fas activated by the inhibition of stem cell factor/KIT signaling in murine melanocyte precursors. J Invest Dermatol, 2005, 124 : 229-234.
[16]Ito M, Kawa Y, Ono H, et al. Removal of stem cell factor or addition of monoclonal anti c-KIT antibody induces apoptosis in murine melanocyte precursors. J Invest Dermatol, 1999, 112(5):796-801.
[17]Munugalavadla V, Dore LC, Tan BL, et al. Repression of c-kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation. Mol Cell Biol, 2005, 25(15):6747-59.
[18]Ronnstrand L. Signal transduction via the stem cell factor receptor/c-Kit. Cell Mol Life Sci, 2004, 61:2535 -2548.
[19]Gupta PB, Kuperwasser C, Brunet JP, et al. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nature Genet, 2005, 37: 1047–1054.
[20]Imokawa G. Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary disorders. Pigment Cell Res, 2004, 17: 96–110.
[21]Schallreuter KU. Advances in melanocyte basic science research. Dermatol Clin, 2007, 25: 283–291.
[22]Schallreuter KU, Kothari S, Chavan B. Regulation of melanogenesis-controversies and new concepts. Exp Dermatol, 2008, 17:395–404.
[23]Matsunaga N, Virador V, Santis C, et al. In situ localization of Agouti Signal Pro- tein in murine skin using immunohistochemistry with an ASP-specific antibody. Biochem Biophy Res Commu, 2000, 270(1):176-182.
[24]Spencer JD, Chavan B, Marles LK, et al. A novel mechanism in control of human pigmentation by (beta)-melanocyte-stimulating hormone and 7-tetrahydRobiop- terin. J Endocrinol, 2005, 187(2):293–302.
[25]Spritz RA, Chiang P-W, Oiso N, et al. Human and mouse disorders of pigmentatio- n. Curr Opin Genet Dev, 2003, 13:284–289.
[26]Mccallion AS, Chakravarti A. EDNRB?EDN3 and Hirchsprung disease type II. Pigment Cell Res, 2001, 14:161–169.
[27]Shears D, Conlon H, Murakami T, et al. Molecular heterogeneity in two families with auditory pigmentary syndromes: the role of neuroimaging and genetic analysis in deafness. Clin Genet, 2004, 65:384–389.
[28]Wehrle Halller B. The role of Kit l igand in melanocyte development and epider- mal homeostasis. Pigment cell res,2003, 16:287-296.
[29]Richards KA, Fukai K, Oiso N, et al. A novel KIT mutation results in piebaldism with progressive depigmentation. J Am Acad Dermatol, 2001, 44:288-292.
[30]Baxter LL, Hou L, Loftus SK, et al. Spotlight on spotted mice: a review of white spotting mouse mutants and associated human pigmentation disorders. Pigment Cell Res, 2004, 17:215-224.
[31]Tomita Y, Suzuki T. Genetics of pigmentary disorders. Am J Med Genet C Semin Med Genet, 2004, 131C:75–81.
[32]Rees JL. The genetics of sun sensitivity in humans. Am J Hum Genet, 2004, 75: 739–751.
[33]Graf J, Voisey J, Hughes I, et al. Promoter polymorphisms in the MATP(SLC45A2) gene are associated with normal human skin color variation. Hum Mutat, 2007, 28: 710–717.
[34]Goding CR. Melanocytes: the new black. Int J Biochem Cell Biol, 2007, 39: 275–279.
[1]Tosaki H, Kunisada T, Motohashi T, et al. Mice transgenic for Kit (V620A): recapitulation of piebaldism but not progressive depigmentation seen in humans with this mutation[J]. J Invest Dermatol, 2006, 126:1111-1118.
[2]吴宝金. ENU诱导小鼠突变及对部分突变基因的定位克隆[D].扬州大学,2004.
[3]吴培林,尹洪萍,殷黎静,等. Kit无义突变致W-3Bao小鼠生殖腺异常及纯合子贫血死亡[J].动物学研究. 2009, 30(1): 45-52.
[4]龚志锦,詹镕洲著.病理组织制片和染色技术(第一版).上海科学技术出版社. 1994.
[5]Wahlsten D, Metten P, Crabbe JC. Survey of 21 inbred mouse strains in two laboratories reveals that BTBR T/+ tf/tf has severely reduced hippocampal commissure and absent corpus callosum[J]. Brain Res, 2003, 971(1):47-54.
[6]Moy SS, Nadler JJ, Young NB, et al. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains[J]. Behav Brain Res, 2007, 176(1):4-20.
[7]McFarlane HG, Kusek GK, Yang M, et al. Autism-like behavioral phenotypes in BTBR T+tf/J mice[J]. Genes Brain Behav, 2008, 7(2):152-63.
[8]赵辨著.临床皮肤病学(第三版).江苏科学技术出版社. 2001.
[9]Hallsson JH, Favor J, Hodgkinson C, et al. Genomic, transcriptional and mutational analysis of the mouse microphthalmia locus[J]. Genetics, 2000, 155(1):291-300.
[10]Giebel LB, Tripathi RK, Strunk KM, et al. Tyrosinase gene mutations associated with type 1B (‘yellow’) oculocutaneous albinism[J]. Am J Hum Genet, 1991, 48:1159-1167.
[11]Matsunaga J, Dakeishi-Hara M, Tanita M, et al. A splicing mutation of the tyrosinase gene causes yellow oculocutaneous albinism in Japanese patients with a pigmented phenotype[J]. Dermatology, 1999, 199:124-129.
[12]MénaschéG, Ho CH, Sanal O, et al. Griscelli syndrome restricted to hypopigmen- tation results from a melanophilin defect (GS3) or a MYO5AF-exon deletion (GS1)[J]. J Clin Invest, 2003, 112:450-456.
[13]Duhl DMJ, Vrieling H, Miller KA, et al. Neomorphic agouti mutations in obese yellow mice[J]. Nature Genet, 1994, 8:59-65.
[14]Michaud EJ, van Vugt MJ, Bultman SJ, et al. Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage[J]. Genes Dev, 1994, 8:1463-1472.
[15]Argeson AC, Nelson KK, Siracusa LD. Molecular basis of the pleiotropicphenotype of mice carrying the hypervariable yellow (Ahvy) mutation at the agouti locus[J]. Genetics, 1996, 142:557-567.
[16]Wolff GL, Roberts DW, Mountjoy KG. Physiological consequences of ectopic agouti gene expression: the yellow obese mouse syndrome[J]. Physiol Genomics, 1999, 1(3):151-163.
[17]Waterston RH, Lindblad-Toh K, Birney E, et al. Initial sequencing and comparative analysis of the mouse genome[J]. Nature, 2002, 420( 5):520-562.
[1]Flanagan SP. "Nude", a new hairless gene with pleiotropic effects in the mouse [J]. Genet Res, 1966, 8 (3): 295-309.
[2]Sundberg JP, King LE, Bascom C. Animal models for male pattern (androgenetic) alopecia[J]. Eur J Dermatol, 2001, 11 (4): 321-325.
[3]Frank J, Pignata C, Panteleyev AA, et al. Exposing the human nude phenotype[J]. Nature, 1999, 398 (6727): 473-474.
[4]吴宝金,茅慧华,朱洪,等.小鼠39个微卫星的PCR条件及其运用[J].中国实验动物学报, 2003, 11 (4): 216-220.
[5]Joseph Sambrook and Russell DW. Molecular cloning: a labortory manual(third edition). Beijing: Science Press. 2002, 479-483(in Chinese).
[6]Dietrich W, Katz H, Lincoln SE, et al. A genetic map of the mouse suitable for typing intraspecific crosses[J]. Genetics. 1992, 131: 423-447.
[7]Dietrich WF, Miller T, Steen R, et al. A comprehensive genetic map of the mouse genome[J]. Nature. 1996, 380: 149-152.
[8]Leatherbury L, Yu Q, Chatterjee B, et al. A novel mouse model of X-linked cardiac hypertrophy[J]. Am J Physiol Heart Circ Physiol. 2008, 294(6):H2701-11.
[9]Wu BJ, Mao HH, Shao YX, et al. Four kinds of ENU-induced white spot mice and chromo- some locations of the mutant genes[J]. Chinese Science Bulletin. 2003, 48(24): 2658-2664.
[10]Bao-Jin Wu, Yi-Xiang Shao, Hui-Hua Mao, et al. Two kinds of ENU-induced scant hair mice and chromosome locations of the mutant genes[J]. Journal of Dermatological Science. 2004, 36: 149-15.
[11]陈兵,钱晨,刘春,等.遗传性瞳孔异位小鼠及其突变基因的染色体定位[J].眼科研究. 2006, 24(4): 352-355.
[12]邵义祥,吴宝金,薛整风,等.遗传性角膜基质变性小鼠及其突变基因的定位[J].南京师大学报(自然科学版). 2006, 29(2): 99-102.
[13]薛整风,陈兵,茅慧华,等.两种白斑小鼠突变基因的染色体定位[J].四川动物. 2006, 25(3): 468-472.
[14]Yano M, Katayose Y, Ashikari M, et al. Hd1, a major photoperiod sensitivity quantitative trait locus in rice, is closely related to the Arabidopsis flowering time gene CONSTANS[J]. Plant Cell. 2000, 12: 2473-2483.
[15]Monna L, Kitazawa N, Yoshino R, et al. Positional cloning of rice semidwarfing gene, sd-1: Rice“Green Revolution Gene”encodes a mutant enzyme involved in gibberellin synthesis[J]. DNA Res. 2002, 9: 11-17.
[16]Yamanouchi U, Yano M, Lin H X, et al. A rice spotted leaf gene, Spl7, encodes a heat stress transcription factor protein[J]. Proc Natl Acad Sci USA, 2002, 99(11): 7530~7535.
[17]Sung YH, Song J, Lee HW. Functional genomics approach using mice[J]. J Biochem Mol Biol. 2004, 37(1):122-132.
[2]Kunisada T, Yoshida H, Yamazaki H, et al. Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors. Development, 1998, 125(15):2915-2923.
[3]Nakamura M, Tobin DJ, Richards-Smith B, et al. Mutant laboratory mice with abnormalities in pigmentation: Annotated tables. J Dermatol Sci, 2002, 28:1–33.
[4]Slominski A, Wortsman J, Plonka PM, et al. Hair follicle pigmentation. J Invest Dermatol, 2005, 124:13-21.
[5]Raposo G, Marks MS. Melanosomes--dark organelles enlighten endosomal membranetransport. Nat Rev Mol Cell Biol, 2007, 8:786–97.
[6]Hornyak TJ. The developmental biology of melanocytes and its application to understanding human congenital disorders of pigmentation. Adv Dermatol, 2006, 22: 201–218.
[7]Price ER, Fischer DE. Sensorineural deafness and pigmentation genes: melanocytes and the Mitf transcriptional network. Neuron, 2001, 30: 15–18.
[8]Levy C, Khaled M, Fischer DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med, 2006, 12: 406–414.
[9]Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature, 2007, 445: 843–850.
[10]Passeron T, Valencia JC, Bertolotto C, et al. SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation. Proc Natl Acad Sci U S A, 2007, 104:13984–9.
[11]Yamaguchi Y, Hearing VJ, Itami S, et al. Mesenchymal-epithelial interactions in the skin: aiming for site-specific tissue regeneration. J Dermatol Sci, 2005, 40:1–9.
[12]Yoshida H, Kunisada T, Grimm T, et al. Review:melanocyte migration and survival controlled by SCF/c-kit expression. J Invest Dermatol Symp Proc, 2001, 6(1):1-5.
[13]Kunisada T, Lu SZ, Yoshida H, et al. Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor. J Exp Med, 1998, 187(10):1565-1573.
[14]Kawaguchi Y, Mori N, Nakayama A. Kit ( + ) melanocytes seem to contribute to melanocyte proliferation after UV exposure as precursor cells. J Invest Dermatol, 2001, 116 :920– 925.
[15]Kimura S, Kawakami T, Kawa Y, et al. Bcl-2 reduced and fas activated by the inhibition of stem cell factor/KIT signaling in murine melanocyte precursors. J Invest Dermatol, 2005, 124 : 229-234.
[16]Ito M, Kawa Y, Ono H, et al. Removal of stem cell factor or addition of monoclonal anti c-KIT antibody induces apoptosis in murine melanocyte precursors. J Invest Dermatol, 1999, 112(5):796-801.
[17]Munugalavadla V, Dore LC, Tan BL, et al. Repression of c-kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation. Mol Cell Biol, 2005, 25(15):6747-59.
[18]Ronnstrand L. Signal transduction via the stem cell factor receptor/c-Kit. Cell Mol Life Sci, 2004, 61:2535 -2548.
[19]Gupta PB, Kuperwasser C, Brunet JP, et al. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nature Genet, 2005, 37: 1047–1054.
[20]Imokawa G. Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary disorders. Pigment Cell Res, 2004, 17: 96–110.
[21]Schallreuter KU. Advances in melanocyte basic science research. Dermatol Clin, 2007, 25: 283–291.
[22]Schallreuter KU, Kothari S, Chavan B. Regulation of melanogenesis-controversies and new concepts. Exp Dermatol, 2008, 17:395–404.
[23]Matsunaga N, Virador V, Santis C, et al. In situ localization of Agouti Signal Pro- tein in murine skin using immunohistochemistry with an ASP-specific antibody. Biochem Biophy Res Commu, 2000, 270(1):176-182.
[24]Spencer JD, Chavan B, Marles LK, et al. A novel mechanism in control of human pigmentation by (beta)-melanocyte-stimulating hormone and 7-tetrahydRobiop- terin. J Endocrinol, 2005, 187(2):293–302.
[25]Spritz RA, Chiang P-W, Oiso N, et al. Human and mouse disorders of pigmentatio- n. Curr Opin Genet Dev, 2003, 13:284–289.
[26]Mccallion AS, Chakravarti A. EDNRB?EDN3 and Hirchsprung disease type II. Pigment Cell Res, 2001, 14:161–169.
[27]Shears D, Conlon H, Murakami T, et al. Molecular heterogeneity in two families with auditory pigmentary syndromes: the role of neuroimaging and genetic analysis in deafness. Clin Genet, 2004, 65:384–389.
[28]Wehrle Halller B. The role of Kit l igand in melanocyte development and epider- mal homeostasis. Pigment cell res,2003, 16:287-296.
[29]Richards KA, Fukai K, Oiso N, et al. A novel KIT mutation results in piebaldism with progressive depigmentation. J Am Acad Dermatol, 2001, 44:288-292.
[30]Baxter LL, Hou L, Loftus SK, et al. Spotlight on spotted mice: a review of white spotting mouse mutants and associated human pigmentation disorders. Pigment Cell Res, 2004, 17:215-224.
[31]Tomita Y, Suzuki T. Genetics of pigmentary disorders. Am J Med Genet C Semin Med Genet, 2004, 131C:75–81.
[32]Rees JL. The genetics of sun sensitivity in humans. Am J Hum Genet, 2004, 75: 739–751.
[33]Graf J, Voisey J, Hughes I, et al. Promoter polymorphisms in the MATP(SLC45A2) gene are associated with normal human skin color variation. Hum Mutat, 2007, 28: 710–717.
[34]Goding CR. Melanocytes: the new black. Int J Biochem Cell Biol, 2007, 39: 275–279.
[1]Tosaki H, Kunisada T, Motohashi T, et al. Mice transgenic for Kit (V620A): recapitulation of piebaldism but not progressive depigmentation seen in humans with this mutation[J]. J Invest Dermatol, 2006, 126:1111-1118.
[2]吴宝金. ENU诱导小鼠突变及对部分突变基因的定位克隆[D].扬州大学,2004.
[3]吴培林,尹洪萍,殷黎静,等. Kit无义突变致W-3Bao小鼠生殖腺异常及纯合子贫血死亡[J].动物学研究. 2009, 30(1): 45-52.
[4]龚志锦,詹镕洲著.病理组织制片和染色技术(第一版).上海科学技术出版社. 1994.
[5]Wahlsten D, Metten P, Crabbe JC. Survey of 21 inbred mouse strains in two laboratories reveals that BTBR T/+ tf/tf has severely reduced hippocampal commissure and absent corpus callosum[J]. Brain Res, 2003, 971(1):47-54.
[6]Moy SS, Nadler JJ, Young NB, et al. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains[J]. Behav Brain Res, 2007, 176(1):4-20.
[7]McFarlane HG, Kusek GK, Yang M, et al. Autism-like behavioral phenotypes in BTBR T+tf/J mice[J]. Genes Brain Behav, 2008, 7(2):152-63.
[8]赵辨著.临床皮肤病学(第三版).江苏科学技术出版社. 2001.
[9]Hallsson JH, Favor J, Hodgkinson C, et al. Genomic, transcriptional and mutational analysis of the mouse microphthalmia locus[J]. Genetics, 2000, 155(1):291-300.
[10]Giebel LB, Tripathi RK, Strunk KM, et al. Tyrosinase gene mutations associated with type 1B (‘yellow’) oculocutaneous albinism[J]. Am J Hum Genet, 1991, 48:1159-1167.
[11]Matsunaga J, Dakeishi-Hara M, Tanita M, et al. A splicing mutation of the tyrosinase gene causes yellow oculocutaneous albinism in Japanese patients with a pigmented phenotype[J]. Dermatology, 1999, 199:124-129.
[12]MénaschéG, Ho CH, Sanal O, et al. Griscelli syndrome restricted to hypopigmen- tation results from a melanophilin defect (GS3) or a MYO5AF-exon deletion (GS1)[J]. J Clin Invest, 2003, 112:450-456.
[13]Duhl DMJ, Vrieling H, Miller KA, et al. Neomorphic agouti mutations in obese yellow mice[J]. Nature Genet, 1994, 8:59-65.
[14]Michaud EJ, van Vugt MJ, Bultman SJ, et al. Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage[J]. Genes Dev, 1994, 8:1463-1472.
[15]Argeson AC, Nelson KK, Siracusa LD. Molecular basis of the pleiotropicphenotype of mice carrying the hypervariable yellow (Ahvy) mutation at the agouti locus[J]. Genetics, 1996, 142:557-567.
[16]Wolff GL, Roberts DW, Mountjoy KG. Physiological consequences of ectopic agouti gene expression: the yellow obese mouse syndrome[J]. Physiol Genomics, 1999, 1(3):151-163.
[17]Waterston RH, Lindblad-Toh K, Birney E, et al. Initial sequencing and comparative analysis of the mouse genome[J]. Nature, 2002, 420( 5):520-562.
[1]Flanagan SP. "Nude", a new hairless gene with pleiotropic effects in the mouse [J]. Genet Res, 1966, 8 (3): 295-309.
[2]Sundberg JP, King LE, Bascom C. Animal models for male pattern (androgenetic) alopecia[J]. Eur J Dermatol, 2001, 11 (4): 321-325.
[3]Frank J, Pignata C, Panteleyev AA, et al. Exposing the human nude phenotype[J]. Nature, 1999, 398 (6727): 473-474.
[4]吴宝金,茅慧华,朱洪,等.小鼠39个微卫星的PCR条件及其运用[J].中国实验动物学报, 2003, 11 (4): 216-220.
[5]Joseph Sambrook and Russell DW. Molecular cloning: a labortory manual(third edition). Beijing: Science Press. 2002, 479-483(in Chinese).
[6]Dietrich W, Katz H, Lincoln SE, et al. A genetic map of the mouse suitable for typing intraspecific crosses[J]. Genetics. 1992, 131: 423-447.
[7]Dietrich WF, Miller T, Steen R, et al. A comprehensive genetic map of the mouse genome[J]. Nature. 1996, 380: 149-152.
[8]Leatherbury L, Yu Q, Chatterjee B, et al. A novel mouse model of X-linked cardiac hypertrophy[J]. Am J Physiol Heart Circ Physiol. 2008, 294(6):H2701-11.
[9]Wu BJ, Mao HH, Shao YX, et al. Four kinds of ENU-induced white spot mice and chromo- some locations of the mutant genes[J]. Chinese Science Bulletin. 2003, 48(24): 2658-2664.
[10]Bao-Jin Wu, Yi-Xiang Shao, Hui-Hua Mao, et al. Two kinds of ENU-induced scant hair mice and chromosome locations of the mutant genes[J]. Journal of Dermatological Science. 2004, 36: 149-15.
[11]陈兵,钱晨,刘春,等.遗传性瞳孔异位小鼠及其突变基因的染色体定位[J].眼科研究. 2006, 24(4): 352-355.
[12]邵义祥,吴宝金,薛整风,等.遗传性角膜基质变性小鼠及其突变基因的定位[J].南京师大学报(自然科学版). 2006, 29(2): 99-102.
[13]薛整风,陈兵,茅慧华,等.两种白斑小鼠突变基因的染色体定位[J].四川动物. 2006, 25(3): 468-472.
[14]Yano M, Katayose Y, Ashikari M, et al. Hd1, a major photoperiod sensitivity quantitative trait locus in rice, is closely related to the Arabidopsis flowering time gene CONSTANS[J]. Plant Cell. 2000, 12: 2473-2483.
[15]Monna L, Kitazawa N, Yoshino R, et al. Positional cloning of rice semidwarfing gene, sd-1: Rice“Green Revolution Gene”encodes a mutant enzyme involved in gibberellin synthesis[J]. DNA Res. 2002, 9: 11-17.
[16]Yamanouchi U, Yano M, Lin H X, et al. A rice spotted leaf gene, Spl7, encodes a heat stress transcription factor protein[J]. Proc Natl Acad Sci USA, 2002, 99(11): 7530~7535.
[17]Sung YH, Song J, Lee HW. Functional genomics approach using mice[J]. J Biochem Mol Biol. 2004, 37(1):122-132.