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

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)b 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 TGFb and SHH signaling. STEM CELLS 2015;33:2496-2508 SIGNIFICANCE STATEMENTMesenchymal stem cells (MSC) are potent and promising immunomodulatory cell therapy that have progressed into the clinic for allotransplantation. Cytokine modified MSC show superior immunosuppressive properties compared to unmodified MSC. In this study, we describe the enhanced immunosuppressive properties of MSC generated under the influence of the proinflammatory cytokine interleukin-17A (MSC-17) compared to interferon-gamma pre-treated MSC (MSC-c). Specifically these human MSC-17 have translational potential in transplantation protocols because they do not express MHC class II, thereby reducing their immunogenicity, in addition to avidly promote the formation of induced T regulatory cells.

Noggin 1 overexpression in retinal progenitors affects bipolar cell generation

“…3 L,M). These data support our previous work in which we showed a role for noggin 1 in the acquisition of retinal identity in ACES cells, but not in the proliferation of retinal progenitors (Messina et al, 2015).…”

“…Noggin 4 was shown to be unable to antagonize BMPs and recover ventralized embryos (Molina et al, 2011). Instead, noggin 1 contributes to forebrain organization and is able to drive ACES cells toward a diencephalic/retinal fate in vitro (Lan et al, 2009;Viczian et al, 2009;Messina et al, 2015). We also hypothesized that noggin may contribute to the maintenance of retinal structure and function in the adult vertebrate eye (Messina et al, 2014).…”

“…Previous studies have analysed noggin 1 role starting from the initial phases of Xenopus development (Smith and Harland, 1992;Bayramov et al, 2011) or in ex-vivo experiments using animal cap explants (Zuber et al, 2003;Lan et al, 2009;Viczian et al;2009;Wong et al, 2015;Messina et al, 2015). No data are reported for a possible role of noggin 1 in later stages of eye development in vivo, however.…”

“…cDNAs (1 mg) were prepared using SuperScript VILO cDNA synthesis Kit (11754250; Life Technologies). RT-qPCR experiments were performed in a CFX384 thermocycler (Bio-Rad) using SYBR Fast Universal Ready Mix Kit (KK4601; Kapa Biosystems) according to Messina et al, (2015). Data were analysed using Bio-Rad CFX manager software (Bio-Rad).…”

“…In the last ten years, noggin 1 was also shown to contribute to the activation of EFTFs in Xenopus laevis pluripotent animal cap embryonic stem (ACES) cells (Zuber et al, 2003;Lan et al, 2009;Viczian et al, 2009). The overexpression of high levels of noggin 1 activates Nodal/TGFb and Shh pathways in ACES cells eliciting a retinal fate in vitro, and these cells are able to induce the formation of a normal eye after transplantation in the eye field region (Lan et al, 2009;Messina et al, 2015). Similar results were obtained treating ACES cells with Noggin protein (Viczian et al, 2009).…”