Noggin-Mediated Retinal Induction Reveals a Novel Interplay Between Bone Morphogenetic Protein Inhibition, Transforming Growth Factor β, and Sonic Hedgehog Signaling

Stem Cells. 2015 Aug;33(8):2496-508. doi: 10.1002/stem.2043. Epub 2015 May 26.

Abstract

It has long been known that the depletion of bone morphogenetic protein (BMP) is one of the key factors necessary for the development of anterior neuroectodermal structures. However, the precise molecular mechanisms that underlie forebrain regionalization are still not completely understood. Here, we show that Noggin1 is involved in the regionalization of anterior neural structures in a dose-dependent manner. Low doses of Noggin1 expand prosencephalic territories, while higher doses specify diencephalic and retinal regions at the expense of telencephalic areas. A similar dose-dependent mechanism determines the ability of Noggin1 to convert pluripotent cells in prosencephalic or diencephalic/retinal precursors, as shown by transplant experiments and molecular analyses. At a molecular level, the strong inhibition of BMP signaling exerted by high doses of Noggin1 reinforces the Nodal/transforming growth factor (TGF)β signaling pathway, leading to activation of Gli1 and Gli2 and subsequent activation of Sonic Hedgehog (SHH) signaling. We propose a new role for Noggin1 in determining specific anterior neural structures by the modulation of TGFβ and SHH signaling.

Keywords: BMP inhibition; Forebrain patterning; Retinal induction; Sonic Hedgehog signaling; Transforming growth factor β signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Pluripotent Stem Cells / metabolism*
  • Retina / cytology
  • Retina / embryology*
  • Signal Transduction / physiology*
  • Telencephalon / cytology
  • Telencephalon / embryology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism
  • Xenopus laevis

Substances

  • Bone Morphogenetic Proteins
  • Carrier Proteins
  • Hedgehog Proteins
  • Shh protein, Xenopus
  • Transforming Growth Factor beta
  • Xenopus Proteins
  • noggin protein