The D1x5 and D1x6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development
The D1x5 and D1x6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development
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DOI：
10.1101/gad.988402
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发表时间：
2002-05-01
影响因子：
10.5
通讯作者：
Lufkin, T
中科院分区：
文献类型：
--
作者：
Robledo, RF;Rajan, L;Lufkin, T
Dlx同源盒基因是果蝇Distal-less（Dll）基因的哺乳动物同源物。Dlx/Dll基因家族是古老的起源，似乎在几乎所有已被鉴定的物种中的附肢发育中发挥作用。在果蝇中，Dll在发育中的附属物的远端部分中表达，并且对于远端结构的发育至关重要。此外，人类Dlx 5和Dlx 6同源框基因已被确定为可能的候选基因的常染色体显性形式的裂手/裂足畸形（SHFM），一种异质性肢体疾病的特征是缺失的中央数字和爪样远端四肢。在小鼠中Dlx 5和Dlx 6基因的靶向失活导致严重的颅面、中轴和无骨骨骼异常，导致围产期致死。首次，Dlx/Dll基因产物被证明是哺乳动物肢体发育的关键调节因子，作为组合的功能丧失突变表型SHFM。此外，在Dlx 5/6缺失小鼠的顶端外胚层嵴中Dlx 5的时空特异性转基因过表达可以完全拯救肢体生长中的D/x/Dll功能。
Dlx homeobox genes are mammalian homologs of the Drosophila Distal-less (Dll) gene. The Dlx/Dll gene family is of ancient origin and appears to play a role in appendage development in essentially all species in which it has been identified. In Drosophila, Dll is expressed in the distal portion of the developing appendages and is critical for the development of distal structures. In addition, human Dlx5 and Dlx6 homeobox genes have been identified as possible candidate genes for the autosomal dominant form of the split-hand/split-foot malformation (SHFM), a heterogeneous limb disorder characterized by missing central digits and claw-like distal extremities. Targeted inactivation of Dlx5 and Dlx6 genes in mice results in severe craniofacial, axial, and appendicular skeletal abnormalities, leading to perinatal lethality. For the first time, Dlx/Dll gene products are shown to be critical regulators of mammalian limb development, as combined loss-of-function mutations phenocopy SHFM. Furthermore, spatiotemporal-specific transgenic overexpression of Dlx5, in the apical ectodermal ridge of Dlx5/6 null mice can fully rescue D/x/Dll function in limb outgrowth.