Ectopic Meis1 expression in the mouse limb bud alters P-D patterning in a Pbx1-independent manner
Ectopic Meis1 expression in the mouse limb bud alters P-D patterning in a Pbx1-independent manner
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DOI：
10.1387/ijdb.072430nm
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发表时间：
2009-01-01
影响因子：
0.7
通讯作者：
Torres, Miguel
中科院分区：
文献类型：
--
作者：
Mercader, Nadia;Selleri, Licia;Torres, Miguel
在肢体发育期间，同源框转录因子Meis1的表达被维甲酸激活，在最近端的肢芽区域，形成上前肢和后肢。早期将肢芽分为近端MEIS阳性和远端MEIS阴性区域对于鸡的正确近端-远端(P-D)肢体发育是必要的，因为异位MEIS1过表达会取消远端肢体结构，产生肢体身份沿P-D轴的近端移位，并接近远端肢体细胞的亲和力。为了确定哺乳动物的P-D肢体规范是否也需要MEIS活性，我们在MSX2启动子的控制下，在远端肢体间充质中异位表达MEIS1的转基因小鼠。MSX2：Meis1转基因小鼠表现出P-D模式的改变和P-D Hox基因表达结构域的移位，类似于之前对鸡的描述。MEIS蛋白与PBX因子协同工作，PBX因子是另一个同源结构域亚家族。MEIS-PBX相互作用是这两种蛋白质在细胞培养中的核定位所必需的，并且对于它们的DNA结合和反式激活效率是重要的。在肢体发育过程中，Pbx1核表达与MEIS表达结构域相关，Pbx1被认为是MEIS的主要伙伴；然而，我们发现Pbx1缺乏并没有改变MSX2：Meis1小鼠的肢体表型。我们的结果表明，MEIS活动在四足动物肢体的P-D规范中起着保守的作用，并表明在这种情况下PBX功能不是必需的，或者是由PBX1以外的合作伙伴提供的。
During limb development, expression of the TALE homeobox transcription factor Meis1 is activated by retinoic acid in the proximal-most limb bud regions, which give rise to the upper forelimb and hindlimb. Early subdivision of the limb bud into proximal Meis-positive and distal Meis-negative domains is necessary for correct proximo-distal (P-D) limb development in the chick, since ectopic Meis1 overexpression abolishes distal limb structures, produces a proximal shift of limb identities along the P-D axis, and proximalizes distal limb cell affinity properties. To determine whether Meis activity is also required for P-D limb specification in mammals, we generated transgenic mice ectopically expressing Meis1 in the distal limb mesenchyme under the control of the Msx2 promoter. Msx2:Meis1 transgenic mice display altered P-D patterning and shifted P-D Hox gene expression domains, similar to those previously described for the chicken. Meis proteins function in cooperation with PBX factors, another TALE homeodomain subfamily. Meis-Pbx interaction is required for nuclear localization of both proteins in cell culture, and is important for their DNA-binding and transactivation efficiency. During limb development, Pbx1 nuclear expression correlates with the Meis expression domain, and Pbx1 has been proposed as the main Meis partner in this context; however, we found that Pbx1 deficiency did not modify the limb phenotype of Msx2:Meis1 mice. Our results indicate a conserved role of Meis activity in P-D specification of the tetrapod limb and suggest that Pbx function in this context is either not required or is provided by partners other than Pbx1.