Compagni Amelia, Logan Malcolm, Klein Rüdiger, Adams Ralf H
Cancer Research UK London Research Institute, Vascular Development Laboratory, WC2A 3PX, London, United Kingdom.
Dev Cell. 2003 Aug;5(2):217-30. doi: 10.1016/s1534-5807(03)00198-9.
We report that targeted inactivation of the Eph receptor ligand ephrinB1 in mouse caused perinatal lethality, edema, defective body wall closure, and skeletal abnormalities. In the thorax, sternocostal connections were arranged asymmetrically and sternebrae were fused, defects that were phenocopied in EphB2/EphB3 receptor mutants. In the wrist, loss of ephrinB1 led to abnormal cartilage segmentation and the formation of additional skeletal elements. We conclude that ephrinB1 and B class Eph receptors provide positional cues required for the normal morphogenesis of skeletal elements. Another malformation, preaxial polydactyly, was exclusively seen in heterozygous females in which expression of the X-linked ephrinB1 gene was mosaic, so that ectopic EphB-ephrinB1 interactions led to restricted cell movements and the bifurcation of digital rays. Our findings suggest that differential cell adhesion and sorting might be relevant for an unusual class of X-linked human genetic disorders, in which heterozygous females show more severe phenotypes than hemizygous males.
我们报道，在小鼠中靶向失活Eph受体配体ephrinB1会导致围产期致死、水肿、体壁闭合缺陷和骨骼异常。在胸部，胸骨肋连接不对称排列且胸骨节融合，这些缺陷在EphB2/EphB3受体突变体中也有类似表现。在腕部，ephrinB1缺失导致软骨分割异常并形成额外的骨骼元素。我们得出结论，ephrinB1和B类Eph受体为骨骼元素的正常形态发生提供了位置线索。另一种畸形，即轴前多指畸形，仅在杂合子雌性中出现，其中X连锁的ephrinB1基因表达呈嵌合状态，因此异位的EphB-ephrinB1相互作用导致细胞运动受限和指骨分叉。我们的研究结果表明，差异细胞黏附和分选可能与一类特殊的X连锁人类遗传疾病有关，其中杂合子雌性比半合子雄性表现出更严重的表型。
