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首页> 外文期刊>Development >Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation.
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Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation.

机译：在骨骼模式和软骨细胞增殖和分化过程中对Pbx1的需求。

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Pbx1 and a subset of homeodomain proteins collaboratively bind DNA as higher-order molecular complexes with unknown consequences for mammalian development. Pbx1 contributions were investigated through characterization of Pbx1-deficient mice. Pbx1 mutants died at embryonic day 15/16 with severe hypoplasia or aplasia of multiple organs and widespread patterning defects of the axial and appendicular skeleton. An obligatory role for Pbx1 in limb axis patterning was apparent from malformations of proximal skeletal elements, but distal structures were unaffected. In addition to multiple rib and vertebral malformations, neural crest cell-derived skeletal structures of the second branchial arch were morphologically transformed into elements reminiscent of first arch-derived cartilages. Although the skeletal malformations did not phenocopy single or compound Hox gene defects, they were restricted to domains specified by Hox proteins bearing Pbx dimerization motifs and unaccompanied by alterations in Hox gene expression. In affected domains of limbs and ribs, chondrocyte proliferation was markedly diminished and there was a notable increase of hypertrophic chondrocytes, accompanied by premature ossification of bone. The pattern of expression of genes known to regulate chondrocyte differentiation was not perturbed in Pbx1-deficient cartilage at early days of embryonic skeletogenesis, however precocious expression of Col1a1, a marker of bone formation, was found. These studies demonstrate a role for Pbx1 in multiple developmental programs and reveal a novel function in co-ordinating the extent and/or timing of proliferation with terminal differentiation. This impacts on the rate of endochondral ossification and bone formation and suggests a mechanistic basis for most of the observed skeletal malformations.
机译：Pbx1和同源结构域蛋白的一个子集将DNA结合为高阶分子复合物，对哺乳动物的发育产生未知的后果。通过鉴定缺乏Pbx1的小鼠来研究Pbx1的贡献。 Pbx1突变体在胚胎第15/16天死亡，伴有严重的发育不全或多个器官发育不全，以及轴和阑尾骨骼的广泛构图缺陷。 Pbx1在肢体轴构图中的强制性作用从近端骨骼元件的畸形显而易见，但远端结构未受影响。除了多处肋骨和椎骨畸形外，第二branch弓神经rest细胞衍生的骨骼结构在形态上也转变为让人联想到第一arch弓软骨的元素。尽管骨骼畸形没有表现出单个或复合Hox基因缺陷的表型，但它们仅限于由带有Pbx二聚化基序的Hox蛋白指定的域，并且不伴有Hox基因表达的改变。在患肢和肋骨的受累区域，软骨细胞增殖明显减少，肥大软骨细胞显着增加，并伴有骨过早骨化。在胚胎骨骼形成的早期，Pbx1缺陷型软骨中未干扰已知调节软骨细胞分化的基因的表达模式，但是发现了早熟的Col1a1表达，这是骨形成的标志。这些研究证明了Pbx1在多个发育程序中的作用，并揭示了在协调增殖与终末分化的程度和/或时间方面的新功能。这会影响软骨内骨化和骨形成的速度，并为大多数观察到的骨骼畸形提供了机械基础。

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