BMP signaling participates in late phase differentiation of the retina, partly via upregulation of Hey2

Abstract

Bone morphogenetic protein (BMP) plays pivotal roles in early retinal development. However, its roles in the late phase of retinal development remain unclear. We found that BMP receptors and ligands were expressed in the postnatal mouse retina. Furthermore, immunostaining revealed that phosphorylated Smads were enriched in various cells types in the inner nuclear layer postnatally. However, phosphorylated Smads were not detected in photoreceptors, suggesting that BMP may play roles in retinal cells in the inner nuclear layer. Forced expression of constitutively active BMP receptors during retinal development resulted in an increased number of bipolar cells and Müller glia and a decreased number of rod photoreceptors; however, proliferation was not perturbed. The expression of dominant negative BMP receptors resulted in a decreased number of Müller glia and bipolar cells. In addition, inhibiting BMP signaling in retinal monolayer cultures abrogated Müller glial process extension, suggesting that BMP signaling also plays a role in the maturation of Müller glia. The expression of the basic helix-loop-helix transcription factor Hey2 was induced by BMP signaling in retinas. The coexpression of sh-Hey2 with constitutively active BMP receptors suggested that the effects of BMP signaling on retinal differentiation could be attributed partly to the induction of Hey2 by BMP. We propose that BMP signaling plays pivotal roles in the differentiation of retinal progenitor cells into late differentiating retinal cell types and in the maturation of Müller glia; these effects were mediated, at least in part, by Hey2.

A transient wave of BMP signaling in the retina is necessary for Müller glial differentiation

“…S9A " type="url"/> ), suggesting that these transcription factors are not downstream of BMP signaling. Kuribayashi et al (2014 ) recently reported that BMP induces an expression of the basic helix-loop-helix (bHLH) transcription factor Hey2 during early retinal development (E17), and proposed that Hey2 might affect Müller glial development ( Kuribayashi et al, 2014 ). We did not observe a decrease in Hey2 expression when we inhibited BMP signaling in P6 retinal explants ( …”

“…However, the presence of Müller glia was assessed in this study by QR1 (Nqo1 – Mouse Genome Informatics) labeling (an extracellular matrix molecule specifically expressed in Müller glia); it is possible that the Müller glia were present but downregulated this differentiation marker, similar to GS or Cralbp in the present study. More recently, Kuribayashi et al found that overexpression of BMPR1a/b in E17 retinas led to an increase in the number of Müller glia, bipolar cells and amacrine cells, and a decrease in photoreceptors in vitro , whereas expression of dominant negative BMPR1a/b at E17 decreased the number of Müller glia and bipolar cells ( Kuribayashi et al, 2014 ). We did not observe any difference in the number of Müller glia, bipolar cells, amacrine cells and ganglion cells when BMP-Smad1/5/8 was inhibited in vivo at P6.…”

“…Several studies have reported that, like in astrocytes, CNTF/LIF signaling promotes Müller glial differentiation during retinal development ( Goureau et al, 2004 ; Rhee and Yang, 2010 ); however, the role of BMP signaling in Müller glial differentiation is less clear. Blocking or activating BMP signaling in chick ( Huillard et al, 2005 ) or mouse embryos ( Kuribayashi et al, 2014 ) leads to a loss or increase in the number of Müller glia, respectively. However, these studies concluded that the effects of BMP were on the retinal progenitors rather than on Müller glia.…”

Stem cell therapies for retinal diseases: recapitulating development to replace degenerated cells

“…The distal domain and its overlaying surface ectoderm become thickened and invaginated, forming the inner layer of the optic cup and the lens vesicle, respectively. Inductive signals including fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs) from the overlaying lens placode drive the inner layer of the optic cup towards becoming NR (Kuribayashi et al, 2014;Pandit et al, 2015;Pittack et al, 1997;Zhao et al, 2001). The proximal domain of the optic vesicle becomes the outer layer of the optic cup and develops into the RPE layer under the influence of the extraocular mesenchyme and the nearby overlying surface ectoderm (Fuhrmann et al, 2000;Muller et al, 2007).…”

Noggin 1 overexpression in retinal progenitors affects bipolar cell generation

“…We reported a slight but significant reduction in the number of bipolar cells in the INL of noggin 1-electroporated retinae with respect to GFP only retinae, but no significant differences were detected in the differentiation of other retinal subpopulations. Recently, two independent studies showed that a BMP wave is necessary to specify cells located in the INL of the mouse retina (Kuribayashi et al, 2014;Ueki et al, 2015), but no data are available for other vertebrates. Kuribayashi and collaborators (2014) showed that the overexpression of BMPs or BMP receptors increased the number of Müller glia and bipolar cells at the expense of rods, supporting the idea that BMPs play a pivotal role in the maturation of these two retinal cell types.…”