Division of Biological Sciences, Section of Cell and Developmental Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, Dresden 01307, Germany; Max Planck Institute for the Physics of Complex Systems, Nothnitzerstraße 38, Dresden 01187, Germany.
Curr Biol. 2022 Jan 24;32(2):289-303.e6. doi: 10.1016/j.cub.2021.10.063. Epub 2021 Nov 17.
Despite the great diversity of vertebrate limb proportion and our deep understanding of the genetic mechanisms that drive skeletal elongation, little is known about how individual bones reach different lengths in any species. Here, we directly compare the transcriptomes of homologous growth cartilages of the mouse (Mus musculus) and bipedal jerboa (Jaculus jaculus), the latter of which has "mouse-like" arms but extremely long metatarsals of the feet. Intersecting gene-expression differences in metatarsals and forearms of the two species revealed that about 10% of orthologous genes are associated with the disproportionately rapid elongation of neonatal jerboa feet. These include genes and enriched pathways not previously associated with endochondral elongation as well as those that might diversify skeletal proportion in addition to their known requirements for bone growth throughout the skeleton. We also identified transcription regulators that might act as "nodes" for sweeping differences in genome expression between species. Among these, Shox2, which is necessary for proximal limb elongation, has gained expression in jerboa metatarsals where it has not been detected in other vertebrates. We show that Shox2 is sufficient to increase mouse distal limb length, and a nearby putative cis-regulatory region is preferentially accessible in jerboa metatarsals. In addition to mechanisms that might directly promote growth, we found evidence that jerboa foot elongation may occur in part by de-repressing latent growth potential. The genes and pathways that we identified here provide a framework to understand the modular genetic control of skeletal growth and the remarkable malleability of vertebrate limb proportion.
尽管脊椎动物肢体比例存在巨大差异，而且我们对驱动骨骼伸长的遗传机制也有了深入的了解，但对于在任何物种中，单个骨骼如何达到不同的长度，我们知之甚少。在这里，我们直接比较了小鼠（Mus musculus）和两足跳鼠（Jaculus jaculus）同源生长软骨的转录组，后者的手臂具有“类似老鼠”的特征，但脚部的跖骨却非常长。两种物种的跖骨和前臂的基因表达差异相交表明，大约 10%的同源基因与新生跳鼠脚部不成比例的快速伸长有关。这些基因和富集的途径以前与软骨内伸长无关，也与除了已知的骨骼生长所需的基因和途径之外，还可能使骨骼比例多样化有关。我们还鉴定了转录调节因子，它们可能作为物种间基因组表达差异的“节点”。其中，Shox2 对于近端肢体伸长是必需的，它在跳鼠跖骨中表达，而在其他脊椎动物中没有检测到。我们表明 Shox2 足以增加小鼠的远端肢体长度，并且在跳鼠跖骨中，附近的一个假定顺式调控区更容易接近。除了可能直接促进生长的机制外，我们还发现证据表明，跳鼠脚的伸长可能部分是通过去抑制潜在的生长潜力来实现的。我们在这里鉴定的基因和途径为理解骨骼生长的模块化遗传控制和脊椎动物肢体比例的显著可变性提供了一个框架。
