Kuijper Sanne, Beverdam Annemiek, Kroon Carla, Brouwer Antje, Candille Sophie, Barsh Gregory, Meijlink Frits
Hubrecht Laboratory, The Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
Development. 2005 Apr;132(7):1601-10. doi: 10.1242/dev.01735. Epub 2005 Feb 23.
The diverse cellular contributions to the skeletal elements of the vertebrate shoulder and pelvic girdles during embryonic development complicate the study of their patterning. Research in avian embryos has recently clarified part of the embryological basis of shoulder formation. Although dermomyotomal cells provide the progenitors of the scapular blade, local signals appear to have an essential guiding role in this process. These signals differ from those that are known to pattern the more distal appendicular skeleton. We have studied the impact of Tbx15, Gli3, Alx4 and related genes on formation of the skeletal elements of the mouse shoulder and pelvic girdles. We observed severe reduction of the scapula in double and triple mutants of these genes. Analyses of a range of complex genotypes revealed aspects of their genetic relationship, as well as functions that had been previously masked due to functional redundancy. Tbx15 and Gli3 appear to have synergistic functions in formation of the scapular blade. Scapular truncation in triple mutants of Tbx15, Alx4 and Cart1 indicates essential functions for Alx4 and Cart1 in the anterior part of the scapula, as opposed to Gli3 function being linked to the posterior part. Especially in Alx4/Cart1 mutants, the expression of markers such as Pax1, Pax3 and Scleraxis is altered prior to stages when anatomical aberrations are visible in the shoulder region. This suggests a disorganization of the proximal limb bud and adjacent flank mesoderm, and is likely to reflect the disruption of a mechanism providing positional cues to guide progenitor cells to their destination in the pectoral girdle.
在胚胎发育过程中，脊椎动物肩部和骨盆带骨骼元素的细胞来源多样，这使得对其模式形成的研究变得复杂。最近对鸟类胚胎的研究阐明了肩部形成的部分胚胎学基础。虽然皮肌节细胞提供了肩胛骨的祖细胞，但局部信号似乎在这个过程中起着至关重要的引导作用。这些信号与已知的在更远端的附属骨骼模式形成中起作用的信号不同。我们研究了Tbx15、Gli3、Alx4及相关基因对小鼠肩部和骨盆带骨骼元素形成的影响。我们观察到这些基因的双突变体和三突变体中肩胛骨严重减少。对一系列复杂基因型的分析揭示了它们的遗传关系，以及由于功能冗余而先前被掩盖的功能。Tbx15和Gli3似乎在肩胛骨的形成中具有协同功能。Tbx15、Alx4和Cart1三突变体中的肩胛骨截断表明Alx4和Cart1在肩胛骨前部具有重要功能，而Gli3的功能与后部相关。特别是在Alx4/Cart1突变体中，在肩部区域出现解剖学异常之前的阶段，Pax1、Pax3和Scleraxis等标记物的表达就发生了改变。这表明近端肢体芽和相邻侧翼中胚层的组织紊乱，并且可能反映了一种机制的破坏，该机制提供位置线索以引导祖细胞到达其在胸带中的目的地。
