Selleri L, Depew M J, Jacobs Y, Chanda S K, Tsang K Y, Cheah K S, Rubenstein J L, O'Gorman S, Cleary M L
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Development. 2001 Sep;128(18):3543-57. doi: 10.1242/dev.128.18.3543.
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.
Pbx1与一部分同源结构域蛋白作为高阶分子复合物协同结合DNA，这对哺乳动物发育的影响尚不清楚。通过对Pbx1基因缺陷小鼠的特征分析来研究Pbx1的作用。Pbx1突变体在胚胎第15/16天死亡，伴有多个器官的严重发育不全或发育不全以及轴向和附属骨骼广泛的模式缺陷。从近端骨骼元素的畸形可以明显看出Pbx1在肢体轴模式形成中起关键作用，但远端结构未受影响。除了多个肋骨和椎骨畸形外，第二鳃弓神经嵴细胞衍生的骨骼结构在形态上转变为类似于第一鳃弓衍生软骨的元素。虽然骨骼畸形并非单个或复合Hox基因缺陷的表型，但它们局限于由带有Pbx二聚化基序的Hox蛋白指定的区域，且未伴随Hox基因表达的改变。在四肢和肋骨的受影响区域，软骨细胞增殖明显减少，肥大软骨细胞显著增加，同时伴有骨的过早骨化。在胚胎骨骼发生早期，已知调节软骨细胞分化的基因表达模式在Pbx1缺陷软骨中并未受到干扰，然而却发现了骨形成标志物Col1a1的早熟表达。这些研究证明了Pbx1在多个发育程序中的作用，并揭示了其在协调增殖程度和/或时间与终末分化方面的新功能。这影响了软骨内骨化和骨形成的速率，并为大多数观察到的骨骼畸形提供了一个机制基础。
