Transcription factors in melanocyte development: distinct roles for Pax-3 and Mitf
Transcription factors in melanocyte development: distinct roles for Pax-3 and Mitf
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DOI：
10.1016/s0925-4773(00)00569-4
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发表时间：
2001-03-01
影响因子：
2.6
通讯作者：
Ziff, EB
中科院分区：
文献类型：
--
作者：
Hornyak, TJ;Hayes, DJ;Ziff, EB
使用转基因小鼠模型来检查鼠转录因子Pax-3和Mitf在黑素细胞发育中的作用。产生了从多巴色素互变异构酶（Dct）启动子表达β-半乳糖苷酶的转基因小鼠，并发现早在胚胎第（E）9.5天就在发育中的成黑素细胞中表达转基因。这些小鼠以内源性Dct表达的模式特征表达转基因。将转基因小鼠与两种鼠毛色突变体Spotch（Sp）杂交。在鼠Pax 3基因中含有突变，和在碱性-螺旋-环-螺旋-亮氨酸拉链基因Mitf中含有突变的Mitf（mi）。将转基因杂合突变体动物杂交以产生转基因胚胎用于分析。突变胚胎中表达β-半乳糖苷酶的成黑素细胞的检查表明，Mitf是成黑素细胞在体内存活到神经嵴发育中的迁移分期区所必需的。对Mitf（mi）/+胚胎的检查表明，在黑素细胞发育的早期，处于杂合状态的成黑素细胞的数量减少。与基因剂量依赖性对细胞存活的影响一致。然而，在迁移阶段期间成黑素细胞生长的定量和分析表明，与Mitf（mi）/Mitf（mi）胚胎相比，杂合胚胎中成黑素细胞的数量增加得更快。Sp/Sp胚胎表现出沿着成黑素细胞迁移途径迁移到特征位置的成黑素细胞，但与对照同窝仔相比，其数量大大减少。一起这些结果支持了黑素细胞发育的模型，其中Pax 3需要在发育早期扩增定向成黑素细胞或受限祖细胞的库，而Mitf以基因剂量依赖性方式促进成黑素细胞在背神经管内和从背神经管迁移后立即存活。并且还可以直接或间接地影响在背外侧通路迁移期间成黑素细胞数目增加的速率。(C)2001爱思唯尔科学爱尔兰有限公司保留所有权利。
A transgenic mouse model was used to examine the roles of the murine transcription factors Pax-3 and Mitf in melanocyte development. Transgenic mice expressing beta -galactosidase from the dopachrome tautomerase (Dct) promoter were generated and found to express the transgene in developing melanoblasts as early as embryonic day (E) 9.5. These mice express the transgene in a pattern characteristic of endogenous Dct expression. Transgenic mice were intercrossed with two murine coat color mutants, Splotch (Sp). containing a mutation in the murine Pax3 gene, and Mitf(mi), with a mutation in the basic-helix-loop-helix-leucine zipper gene Mitf. Transgenic heterozygous mutant animals were crossed to generate transgenic embryos for analysis. Examination of beta -galactosidase-expressing melanoblasts in mutant embryos reveals that Mitf is required in vivo for survival of melanoblasts up to the migration staging area in neural crest development. Examination of Mitf(mi)/+ embryos shows that there are diminished numbers of melanoblasts in the heterozygous state early in melanocyte development. consistent with a gene dosage-dependent effect upon cell survival. However, quantification and analysis of melanoblast growth during the migratory phase suggests that melanoblasts then increase in number more rapidly in the heterozygous embryo, In contrast to Mitf(mi)/Mitf(mi) embryos. Sp/Sp embryos exhibit melanoblasts that have migrated to characteristic locations along the melanoblast migratory pathway, but are greatly reduced in number compared to control littermates. Together. these results support a model for melanocyte development whereby Pax3 is required to expand a pool of committed melanoblasts or restricted progenitor cells early in development, whereas Mitf facilitates survival of the melanoblast in a gene dosage-dependent manner within and immediately after emigration from the dorsal neural tube. and may also directly or indirectly affect the rate at which melanoblast number increases during dorsolateral pathway migration. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.