Neural retina identity is specified by lens-derived BMP signals

Abstract

The eye has served as a classical model to study cell specification and tissue induction for over a century. Nevertheless, the molecular mechanisms that regulate the induction and maintenance of eye-field cells, and the specification of neural retina cells are poorly understood. Moreover, within the developing anterior forebrain, how prospective eye and telencephalic cells are differentially specified is not well defined. In the present study, we have analyzed these issues by manipulating signaling pathways in intact chick embryo and explant assays. Our results provide evidence that at blastula stages, BMP signals inhibit the acquisition of eye-field character, but from neural tube/optic vesicle stages, BMP signals from the lens are crucial for the maintenance of eye-field character, inhibition of dorsal telencephalic cell identity and specification of neural retina cells. Subsequently, our results provide evidence that a Rax2-positive eye-field state is not sufficient for the progress to a neural retina identity, but requires BMP signals. In addition, our results argue against any essential role of Wnt or FGF signals during the specification of neural retina cells, but provide evidence that Wnt signals together with BMP activity are sufficient to induce cells of retinal pigment epithelial character. We conclude that BMP activity emanating from the lens ectoderm maintains eye-field identity, inhibits telencephalic character and induces neural retina cells. Our findings link the requirement of the lens ectoderm for neural retina specification with the molecular mechanism by which cells in the forebrain become specified as neural retina by BMP activity.

Control of lens development by Lhx2-regulated neuroretinal FGFs

“…This same study showed that adding BMP7 or the combination of BMP4 and BMP7 to Lhx2 −/− head cultures was sufficient to induce Sox2 expression in surface ectoderm (Yun et al, 2009). Other studies have also demonstrated an essential role for BMP4/7 signaling in early stages of lens development (Furuta and Hogan, 1998;Murali et al, 2005;Pandit et al, 2015;Wawersik et al, 1999). By contrast, our study indicated FGF signaling as perhaps the major mediator in Lhx2 regulation of lens maturation.…”

Signaling and Gene Regulatory Networks in Mammalian Lens Development

“…In the lens-forming ectoderm, BMP expression is negatively autoregulated [135] and this is independent of Smad1, Smad5, or Smad4 [52]. BMP signals stemming from the lens specify the neuroretina [136], and loss of BMP4 in the optic vesicle is detrimental for lens formation along with the neuroretina being converted into the RPE [54]. It appears that expression of BMPs in the dorsal optic vesicle is stabilized by Wnt signals from the ectoderm via β-catenin-independent and GSK3β-dependent pathway [137].…”

Systems biology of lens development: A paradigm for disease gene discovery in the eye

“…At an earlier stage in chicken, the pre-lens ectoderm is required for optic cup morphogenesis (Hyer et al, 2003). Chicken studies also suggest that lens ectoderm-derived Bmp activity specifies retinal cells (Pandit et al, 2015). Further, Dr. David Beebe’s findings indicate that the lens is necessary for organizing the anterior segment through control of corneal endothelium (Beebe and Coats, 2000).…”