title: Foxa1 and Foxa2 are required for formation of the intervertebral discs.
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.
authors: Molecular Genetics and Microbiology and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida, United States of America.
authors: Jennifer A
authors: JA
authors: Maier
authors: YinTing
authors: Y
authors: Lo
authors: Brian D
authors: BD
authors: Harfe
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D005260:Female; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007403:Intervertebral Disc / Q000196:embryology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D054259:Neural Tube / Q000378:metabolism; D009672:Notochord / Q000196:embryology / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D000098908:Brachyury Protein
chemical_list: D005326:Fetal Proteins; D053823:Hedgehog Proteins; D051541:Hepatocyte Nuclear Factor 3-alpha; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; C489656:Not protein, mouse
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