Abstract
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.
Highlights
Three main structures compose the intervertebral disc (IVD); the annulus fibrosus (AF), the nucleus pulposus (NP), and endplates (EP)
The NP is formed from the embryonic notochord [3] and it is encircled by the AF, a structure comprised of many concentric rings of collagen fibers [1]
Removal of Foxa1 and Foxa2 in the mouse notochord The Foxa1 null allele and the Foxa2 conditional floxed allele have been described previously [26,36]. Mice containing these alleles were crossed to animals containing the ShhcreERT2 allele [38] to generate Foxa1+/2;Foxa2c/c;ShhcreERT2 mice. These animals were phenotypically normal since the ShhcreERT2 allele only produces CRE protein in the presence of tamoxifen
Summary
Three main structures compose the intervertebral disc (IVD); the annulus fibrosus (AF), the nucleus pulposus (NP), and endplates (EP). A disc is sandwiched between each of the vertebrae along the axial skeleton of vertebrates and allows for flexibility while providing a major support to the body. The NP is formed from the embryonic notochord [3] and it is encircled by the AF, a structure comprised of many concentric rings of collagen fibers [1]. Hyaline cartilage endplates bound the disc superiorly and inferiorly and attach each disc to the vertebrae [1,2]. It is through the endplates that the disc, which is avascular and is not innervated by nerves, obtains its nutrients via diffusion [1,2,5]
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