The secreted metalloprotease ADAMTS20 is required for melanoblast survival.
The secreted metalloprotease ADAMTS20 is required for melanoblast survival.
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DOI：
10.1371/journal.pgen.1000003
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发表时间：
2008-02-29
期刊：
影响因子：
4.5
通讯作者：
Pavan WJ
中科院分区：
文献类型：
--
作者：
Silver DL;Hou L;Somerville R;Young ME;Apte SS;Pavan WJ
ADAMTS 20（具有血小板反应蛋白1型基序的去整合素样和金属蛋白酶结构域）是分泌型金属蛋白酶家族的成员，其可以加工多种细胞外基质（ECM）组分和分泌分子。adamts 20基因突变导致bt小鼠背部和腹部出现白色斑点，表明神经嵴（NC）来源的成黑素细胞发育缺陷。Adamts 20在邻近迁移的成黑素细胞的真皮间充质细胞中的表达模式使我们最初提出Adamts 20调节成黑素细胞迁移。然而，使用Dct-LacZ转基因跟踪成黑素细胞的发育，我们确定成黑素细胞正常分布在整个安装E12.5 bt/bt胚胎，但特别是减少在主干的E13.5 bt/bt胚胎由于7倍的凋亡率。在bt/bt动物的新生皮肤和胚胎中，成黑素细胞缺陷加剧，这些动物也是Adamts 9（Adamts 20的密切同源物）的单倍不足，表明这些金属蛋白酶在成黑素细胞发育中功能重叠。我们确定了Adamts 20调节成黑素细胞存活的两种潜在机制。首先，皮肤外植体培养证明Adamts 20是成黑素细胞响应可溶性Kit配体（sKitl）所必需的。为了支持这一要求，bt/bt; Kittm 1Alf/+和bt/bt;KitlSl/+小鼠表现出协同增加的斑点。其次，ADAMTS 20在体外切割聚集的蛋白聚糖多功能蛋白聚糖，并且是体内多功能蛋白聚糖加工所必需的，提高了多功能蛋白聚糖参与成黑素细胞发育的可能性。这些发现揭示了以前未被认识到的作用，Adamts蛋白酶在细胞存活和介导的试剂盒信号在皮肤的成黑素细胞定植。我们的研究结果不仅对理解NC衍生的成黑素细胞发育机制具有意义，而且还为分泌型金属蛋白酶的新生物学功能提供了见解。长期以来，拥有黑色和白色皮毛的老鼠一直是老鼠爱好者和遗传学家的最爱。对小鼠毛色突变体的分析对正常发育途径以及人类疾病过程产生了重要的见解。在这项研究中，我们已经调查了突变的分泌型金属蛋白酶，Adamts 20，导致小鼠的白色带在他们的腰部区域，即使Adamts 20是不表达的色素生产细胞。我们的研究结果表明，带状图案是由于色素细胞死亡增加，色素细胞数量减少的躯干，和密切相关的金属蛋白酶的功能重叠的组合。Adamts 20突变体破坏了Kit的功能，Kit是一种调节色素细胞发育的蛋白质，并且改变了色素细胞周围的细胞外基质。这些发现对我们理解色素细胞发育的一般机制以及分泌型金属蛋白酶的新生物学功能都有意义。
ADAMTS20 (A disintegrin-like and metalloprotease domain with thrombospondin type-1 motifs) is a member of a family of secreted metalloproteases that can process a variety of extracellular matrix (ECM) components and secreted molecules. Adamts20 mutations in belted (bt) mice cause white spotting of the dorsal and ventral torso, indicative of defective neural crest (NC)-derived melanoblast development. The expression pattern of Adamts20 in dermal mesenchymal cells adjacent to migrating melanoblasts led us to initially propose that Adamts20 regulated melanoblast migration. However, using a Dct-LacZ transgene to track melanoblast development, we determined that melanoblasts were distributed normally in whole mount E12.5 bt/bt embryos, but were specifically reduced in the trunk of E13.5 bt/bt embryos due to a seven-fold higher rate of apoptosis. The melanoblast defect was exacerbated in newborn skin and embryos from bt/bt animals that were also haploinsufficient for Adamts9, a close homolog of Adamts20, indicating that these metalloproteases functionally overlap in melanoblast development. We identified two potential mechanisms by which Adamts20 may regulate melanoblast survival. First, skin explant cultures demonstrated that Adamts20 was required for melanoblasts to respond to soluble Kit ligand (sKitl). In support of this requirement, bt/bt;Kittm1Alf/+ and bt/bt;KitlSl/+ mice exhibited synergistically increased spotting. Second, ADAMTS20 cleaved the aggregating proteoglycan versican in vitro and was necessary for versican processing in vivo, raising the possibility that versican can participate in melanoblast development. These findings reveal previously unrecognized roles for Adamts proteases in cell survival and in mediating Kit signaling during melanoblast colonization of the skin. Our results have implications not only for understanding mechanisms of NC-derived melanoblast development but also provide insights on novel biological functions of secreted metalloproteases. Mice with black and white coat coloration patterns have long been favorites of mouse fanciers and geneticists alike. Analysis of mouse coat color mutants has yielded important insights into normal developmental pathways as well as human disease processes. In this study we have investigated how mutations in a secreted metalloprotease, Adamts20, result in mice with white belts in their lumbar region, even though Adamts20 is not expressed in the pigment producing cells. Our findings suggest that the belting pattern is due to a combination of increased pigment cell death, decreased pigment cell number in the trunk, and functional overlap of closely related metalloproteases. Adamts20 mutants have disrupted function of Kit, a protein that regulates pigment cell development, as well as alterations in the extracellular matrix that surrounds the pigment cells. These findings have implications both for our understanding of general mechanisms of pigment cell development as well as for new biological functions of secreted metalloproteases.
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DOI：
10.1073/pnas.88.11.4671
发表时间：
1991-06-01
影响因子：
11.1
作者：
BRANNAN, CI;LYMAN, SD;COPELAND, NG
通讯作者：
COPELAND, NG
影响因子：
4.8
作者：
Dutt, S;Kléber, M;Zimmermann, DR
通讯作者：
Zimmermann, DR
影响因子：
9.2
作者：
Hesselson, D;Newman, C;Kimble, J
通讯作者：
Kimble, J
影响因子：
64.5
作者：
GEISSLER, EN;RYAN, MA;HOUSMAN, DE
通讯作者：
HOUSMAN, DE
影响因子：
2.6
作者：
Henderson, DJ;Ybot-Gonzalez, P;Copp, AJ
通讯作者：
Copp, AJ