Foxa1 and Foxa2 are required for formation of the intervertebral discs.
Foxa1 and Foxa2 are required for formation of the intervertebral discs.
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DOI：
10.1371/journal.pone.0055528
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Harfe BD
中科院分区：
文献类型：
--
作者：
Maier JA;Lo Y;Harfe BD
椎间盘（IVD）由3个主要结构组成，即围绕凝胶状髓核（NP）的胶原纤维环（AF）和附着于椎体的透明软骨终板。IVD位于每个椎体之间。IVD的退化被认为是背痛的主要原因，背痛是一种潜在的慢性疾病，几乎没有有效的治疗方法。NP由胚胎脊索形成。Foxa 1和Foxa 2是叉头盒家族中的转录因子，在脊索发育的早期表达。然而，胚胎致死性和Foxa 2基因敲除小鼠中脊索的缺失排除了这些基因在IVD形成过程中可能发挥的潜在作用的研究。使用条件性Foxa 2等位基因与他莫昔芬诱导的Cre等位基因（ShhcreERT 2），我们从Foxa 1无效的E7.5小鼠的脊索中去除Foxa 2。Foxa1−/−; Foxa2c/c; ShhcreERT 2双突变体动物具有严重变形的髓核，尾部细胞死亡增加，刺猬信号减少，脊索鞘缺陷和神经管的异常背腹图案。仅缺乏Foxa 1或Foxa 2的脊索胚胎与对照动物无法区分，表明这些基因在IVD形成中具有功能冗余。此外，我们还提供了体内遗传学证据，表明Foxa基因是脊索中Shh激活所必需的。
The intervertebral disc (IVD) is composed of 3 main structures, the collagenous annulus fibrosus (AF), which surrounds the gel-like nucleus pulposus (NP), and hyaline cartilage endplates, which are attached to the vertebral bodies. An IVD is located between each vertebral body. Degeneration of the IVD is thought to be a major cause of back pain, a potentially chronic condition for which there exist few effective treatments. The NP forms from the embryonic notochord. Foxa1 and Foxa2, transcription factors in the forkhead box family, are expressed early during notochord development. However, embryonic lethality and the absence of the notochord in Foxa2 null mice have precluded the study of potential roles these genes may play during IVD formation. Using a conditional Foxa2 allele in conjunction with a tamoxifen-inducible Cre allele (ShhcreERT2), we removed Foxa2 from the notochord of E7.5 mice null for Foxa1. Foxa1−/−;Foxa2c/c;ShhcreERT2 double mutant animals had a severely deformed nucleus pulposus, an increase in cell death in the tail, decreased hedgehog signaling, defects in the notochord sheath, and aberrant dorsal-ventral patterning of the neural tube. Embryos lacking only Foxa1 or Foxa2 from the notochord were indistinguishable from control animals, demonstrating a functional redundancy for these genes in IVD formation. In addition, we provide in vivo genetic evidence that Foxa genes are required for activation of Shh in the notochord.
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