Regulation of Mast Cell Differentiation by mi Transcription Factor (MITE)

我们研究了MITF对肥大细胞发育的影响。1）.在编码MITF的mi位点上已经报道了许多突变等位基因。我们研究了突变MITF的结构与突变MITF的生物学效应之间的相互关系。mi是首次发现的突变等位基因，在基本结构域缺失了一个精氨酸。由mi突变等位基因产生的MITF （mi-MITF）缺乏DNA结合潜能。虽然mi-MITF没有转录能力，但它可以与其他转录因子相互作用，抑制其功能（抑制性突变）。tg是一种转基因插入突变，在tg/tg小鼠培养的肥大细胞（cmc）中不产生MITF（零突变）。tg/tg cmc的表型比mi/mi cmc的表型更严重。2）.通过将正常（+/+）或tg/tg小鼠骨髓细胞移植至辐照W/Wv小鼠，考察MITF对肥大细胞发育的必要性。由于多能造血干细胞的缺陷，W/Wv小鼠肥大细胞缺乏。无论是+/+还是tg/tg小鼠的骨髓移植后，红细胞、中性粒细胞、巨噬细胞、B细胞和T细胞都成为供体来源。当注射+/+骨髓细胞时，W/Wv小鼠的所有组织均出现肥大细胞，而当注射tg/tg骨髓细胞时，肥大细胞未出现。在成年小鼠的组织中，MITF似乎是肥大细胞从其前体分化的必要条件。

We investigated the effect of MITF on development of mast cells. 1).Many mutant alleles have been reported in the mi locus that encodes MITF. We examined the interrelationship between the structure of mutant MITF and the biological effect of the mutated MITF. The mi is the firstly found mutant allele, and an arginine was deleted at the basic domain. The MITF produced by the mi mutant allele (mi-MITF) lacks DNA binding potential. Although the mi-MITF has no transcription ability, it can interact with other transcription factors and inhibit their functions (inhibitory mutation). The tg is a transgene insertion mutation, and MITF is not produced in cultured mast cells (CMCs) derived from tg/tg mice (null mutation). The phenotype of tg/tg CMCs was more severe than that of mi/mi CMCs. 2).The necessity of MITF for development of mast cells was examined by grafting bone marrow cells of normal (+/+) or tg/tg mice to irradiated W/Wv mice. W/Wv mice are deficient in mast cells due to the defect of multipotential hematopoietic stem cells. Erythrocytes, neutrophils, macrophages, B cells and T cells became of donor origin after the bone marrow transplantation from either +/+ or tg/tg mice. Mast cells developed in all examined tissues of W/Wv mice when +/+ bone marrow cells were injected, but did not when tg/tg bone marrow cells were injected. MITF appears essential for differentiation of mast cells from their precursors in tissues of adult mice.