Foxa1 and Foxa2 are required for formation of the intervertebral discs

PLoS One. 2013;8(1):e55528. doi: 10.1371/journal.pone.0055528. Epub 2013 Jan 31.

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 (ShhcreER(T2)), we removed Foxa2 from the notochord of E7.5 mice null for Foxa1. Foxa1(-/-);Foxa2(c/c);ShhcreER(T2) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / genetics
  • Female
  • Fetal Proteins / genetics
  • Fetal Proteins / metabolism
  • Gene Knockout Techniques
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Hepatocyte Nuclear Factor 3-alpha / genetics*
  • Hepatocyte Nuclear Factor 3-beta / genetics*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Intervertebral Disc / embryology*
  • Intervertebral Disc / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Neural Tube / metabolism
  • Notochord / embryology
  • Notochord / metabolism
  • Organogenesis / genetics
  • Signal Transduction
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism

Substances

  • Fetal Proteins
  • Foxa1 protein, mouse
  • Foxa2 protein, mouse
  • Hedgehog Proteins
  • Hepatocyte Nuclear Factor 3-alpha
  • Homeodomain Proteins
  • Not protein, mouse
  • T-Box Domain Proteins
  • Hepatocyte Nuclear Factor 3-beta
  • Brachyury protein