Lallemand Yvan, Nicola Marie-Anne, Ramos Casto, Bach Antoine, Cloment Cécile Saint, Robert Benoît
Unité de Génétique Moléculaire de la Morphogenèse, Institut Pasteur, URA 2578 du CNRS, 25 rue du Dr Roux, 75724 Paris, Cedex 15, France.
Development. 2005 Jul;132(13):3003-14. doi: 10.1242/dev.01877. Epub 2005 Jun 1.
The homeobox-containing genes Msx1 and Msx2 are highly expressed in the limb field from the earliest stages of limb formation and, subsequently, in both the apical ectodermal ridge and underlying mesenchyme. However, mice homozygous for a null mutation in either Msx1 or Msx2 do not display abnormalities in limb development. By contrast, Msx1; Msx2 double mutants exhibit a severe limb phenotype. Our analysis indicates that these genes play a role in crucial processes during limb morphogenesis along all three axes. Double mutant limbs are shorter and lack anterior skeletal elements (radius/tibia, thumb/hallux). Gene expression analysis confirms that there is no formation of regions with anterior identity. This correlates with the absence of dorsoventral boundary specification in the anterior ectoderm, which precludes apical ectodermal ridge formation anteriorly. As a result, anterior mesenchyme is not maintained, leading to oligodactyly. Paradoxically, polydactyly is also frequent and appears to be associated with extended Fgf activity in the apical ectodermal ridge, which is maintained up to 14.5 dpc. This results in a major outgrowth of the mesenchyme anteriorly, which nevertheless maintains a posterior identity, and leads to formation of extra digits. These defects are interpreted in the context of an impairment of Bmp signalling.
含同源框基因Msx1和Msx2在肢体形成的最早阶段就在肢体区域高度表达,随后在顶端外胚层嵴及其下方的间充质中均有表达。然而,Msx1或Msx2基因纯合缺失突变的小鼠在肢体发育中并未表现出异常。相比之下,Msx1;Msx2双突变体表现出严重的肢体表型。我们的分析表明,这些基因在肢体沿所有三个轴的形态发生过程中的关键过程中发挥作用。双突变体的肢体较短,且缺少前部骨骼元素(桡骨/胫骨、拇指/拇趾)。基因表达分析证实,不存在具有前部特征的区域形成。这与前部外胚层中背腹边界特化的缺失相关,这阻止了顶端外胚层嵴在前部的形成。结果,前部间充质无法维持,导致少指(趾)畸形。矛盾的是,多指(趾)畸形也很常见,并且似乎与顶端外胚层嵴中Fgf活性的延长有关,这种活性一直维持到胚胎第14.5天。这导致间充质在前部大量生长,不过仍保持后部特征,并导致额外指(趾)的形成。这些缺陷在Bmp信号传导受损的背景下得到解释。