scholarly journals Proteolytic processing of LRP2 on RPE cells regulates BMP activity to control eye size and refractive error

2018 ◽  
Author(s):  
Ross F. Collery ◽  
Brian A. Link
Keyword(s):  
Signaling Pathways ◽  
Refractive Error ◽  
Retinal Pigment ◽  
Bmp Signaling ◽  
Proteolytic Processing ◽  
Fine Tuning ◽  
Rpe Cells ◽  
Eye Growth ◽  
Eye Size ◽  
Multiple Signaling

AbstractMutations in LRP2, a transmembrane receptor, cause ocular enlargement and high-myopia. LRP2 is expressed by the RPE and eye ciliary epithelia, binding many extracellular ligands, including Bmp4 and Shh. Signaling mediated by LRP2 is very context-dependent, and how multiple pathways are coordinated is unknown. Transcriptome analyses of ocular tissues revealed that controlled, sustained BMP signaling from the RPE is critical for normal eye growth and emmetropia (proper refraction). Using zebrafish, we demonstrate that BACE sheddase-dependent LRP2 cleavage produces a soluble domain that binds BMP4, inhibiting its signaling. We propose that controlled proteolytic cleavage of LRP2 makes two ligand-binding receptor forms available: a soluble BMP trap, and a membrane-bound RPE signaling facilitator. By modulating LRP2 cleavage, cells can fine-tune and coordinate multiple signaling pathways, as well as growth and turnover of the extracellular matrix, control of which is important to maintain proper eye size. This data supports the concept that LRP2 acts as a homeostasis node that buffers and integrates diverse signaling to regulate emmetropic eye growth.Author SummaryFor proper focusing and normal vision, the axial length of the eye needs to match the refractive power of the lens. This is achieved by fine-tuning multiple signaling pathways to regulate the shape of the eye primarily by remodeling of the sclera, the outermost layer of the eye. This process is termed emmetropization. Emmetropization cues are initiated by visual input, but how signals are transduced from the photoreceptors across the retinal pigment epithelium to the sclera is incompletely understood. Here we show that cleavage of Lrp2, a large receptor expressed on RPE cells in the eye, alters BMP signaling, which contributes to proper eye size control. Dysregulation of BMP signaling by a) absence of Lrp2 in mutant zebrafish or b) overexpression of BMP antagonists from the RPE both cause eye enlargement and myopia. Understanding how regulated cleavage of Lrp2 affects paracrine signaling provides critical insight to emmetropization, raising the possibility for development of therapeutic agents to combat the epidemic incidence of refractive error.

scholarly journals Analysis of genetic networks regulating refractive eye development in collaborative cross progenitor strain mice reveals new genes and pathways underlying human myopia

2019 ◽  
Author(s):  
Tatiana V. Tkatchenko ◽  
Rupal L. Shah ◽  
Takayuki Nagasaki ◽  
Andrei V. Tkatchenko ◽  
◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Refractive Error ◽  
Genetic Background ◽  
Eye Development ◽  
Continuous Distribution ◽  
Genetic Networks ◽  
Visual Environment ◽  
Eye Growth ◽  
Refractive Development ◽  
The Impact

AbstractPopulation studies suggest that genetic factors play an important role in refractive error development; however, the precise role of genetic background and the composition of the signaling pathways underlying refractive eye development remain poorly understood. Here, we analyzed normal refractive development and susceptibility to form-deprivation myopia in the eight progenitor mouse strains of the Collaborative Cross (CC). Genetic background strongly influenced both baseline refractive development and susceptibility to environmentally-induced myopia. Baseline refractive errors ranged from −21.2 diopters (D) in 129S1/svlmj mice to +22.0 D in CAST/EiJ mice and represented a continuous distribution typical of a quantitative genetic trait. The extent of induced form-deprivation myopia ranged from −5.6 D in NZO/HILtJ mice to −20.0 D in CAST/EiJ mice and also followed a continuous distribution. Whole-genome (RNA-seq) gene expression profiling in retinae from CC progenitor strains identified genes whose expression level correlated with either baseline refractive error or susceptibility to myopia. Expression levels of 2,302 genes correlated with the baseline refractive state of the eye, whereas 1,917 genes correlated with susceptibility to induced myopia. Genome-wide gene-based association analysis in the CREAM and UK Biobank human cohorts revealed that 985 of the above genes were associated with refractive error development in humans, including 847 genes which were implicated in the development of human myopia for the first time. Although the gene sets controlling baseline refractive development and those regulating susceptibility to myopia overlapped, these two processes appeared to be controlled by largely distinct sets of genes. Comparison with data for other animal models of myopia revealed that the genes identified in this study comprise a well-defined set of retinal signaling pathways, which are highly conserved across different species. These results provide attractive targets for the development of anti-myopia drugs.Author SummarySeveral lines of evidence suggest that variations in genetic background have a strong impact on a default (baseline) trajectory of eye growth and refractive development. Many studies also highlighted differences in susceptibility of different individuals to environmentally induced changes in refractive eye development, suggesting that genetic background plays an important role in visual regulation of eye growth. However, genes and signaling pathways that control the baseline trajectory of refractive eye development and those that regulate the impact of visual environment on refractive eye development are still poorly understood. Our data suggest that both processes are regulated by elaborate retinal genetic networks. Surprisingly, we found that although genes that control baseline refractive eye development and genes regulating the impact of visual environment on refractive development overlap, there is a large number of genes and pathways which exclusively control either the baseline trajectory of refractive eye development or the impact of visual environment on refractive development. Moreover, we found that many of the genes and pathways, which we found to be associated with either baseline refractive development or susceptibility to environmentally induced myopia in mice, are also associated with refractive error development in the human population and are highly conserved across different species. Identification of genes and pathways that underlie visual regulation of eye growth versus genes and pathways that control default trajectory of refractive eye development sheds light on the basic mechanisms of eye emmetropization and provides previously unexplored possibilities for the development of new treatment options for myopia.

Patterning the Vertebrate Retina with Morphogenetic Signaling Pathways

2019 ◽  
Vol 26 (2) ◽  
pp. 185-196 ◽  
Author(s):  
Marcos J. Cardozo ◽  
María Almuedo-Castillo ◽  
Paola Bovolenta
Keyword(s):  
Signaling Pathways ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Subsequent Development ◽  
Neural Retina ◽  
Bmp Signaling ◽  
Vertebrate Species ◽  
Optic Stalk ◽  
Optic Cup ◽  
Vertebrate Eye

The primordium of the vertebrate eye is composed of a pseudostratified and apparently homogeneous neuroepithelium, which folds inward to generate a bilayered optic cup. During these early morphogenetic events, the optic vesicle is patterned along three different axes—proximo-distal, dorso-ventral, and naso-temporal—and three major domains: the neural retina, the retinal pigment epithelium (RPE), and the optic stalk. These fundamental steps that enable the subsequent development of a functional eye, entail the precise coordination among genetic programs. These programs are driven by the interplay of signaling pathways and transcription factors, which progressively dictate how each tissue should evolve. Here, we discuss the contribution of the Hh, Wnt, FGF, and BMP signaling pathways to the early patterning of the retina. Comparative studies in different vertebrate species have shown that their morphogenetic activity is repetitively used to orchestrate the progressive specification of the eye with evolutionary conserved mechanisms that have been adapted to match the specific need of a given species.

Multiple Signaling Pathways Control Tbx6 Expression during Xenopus Myogenesis

2004 ◽  
Vol 36 (6) ◽  
pp. 390-396 ◽  
Author(s):  
Pan-Feng Fang ◽  
Rui-Ying Hu ◽  
Xing-Yue He ◽  
Xiao-Yan Ding
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanism ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Paraxial Mesoderm ◽  
Dominant Negative Form ◽  
Multiple Signaling ◽  
Dose Dependent ◽  
Negative Form

Abstract Tbx6 is critical for somite specification and myogenesis initiation. It has been shown that Activin/Nodal, VegT/Nodal, FGF, and BMP signaling pathways are involved early in specifying mesoderm or later in patterning mesoderm, and Xnot plays roles in setting up the boundary between notochord and paraxial mesoderm. In this study, we introduce the dominant negative form of above genes into embryos to evaluate if they are responsible for regulating Tbx6 expression. The results show that: (1) Activin/Nodal and VegT/Nodal signals are necessary for both initiation and maintenance of Tbx6 expression, and Nodal is sufficient to induce ectopic Tbx6 expression; (2) FGF signal is necessary for the initiation and maintenance of Tbx6, but it is not sufficient to induce Tbx6 expression; (3) BMP is also necessary for the expression of Tbx6, and the induction of Tbx6 expression by BMP is dose dependent; (4) Xnot has no effect on the expression of Tbx6. Our results suggest that several signaling pathways are involved in regulating Tbx6 expression, and pave the route to reveal the molecular mechanism of initiating myogenesis.

scholarly journals Changing topography of the RPE resulting from experimentally induced rapid eye growth

1997 ◽  
Vol 14 (3) ◽  
pp. 449-461 ◽  
Author(s):  
Patricia A. Fleming ◽  
Alison M. Harman ◽  
Lyn D. Beazley
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Significant Degree ◽  
Cell Number ◽  
Cell Enlargement ◽  
Average Cell ◽  
Rpe Cells ◽  
Eye Growth ◽  
Eye Opening ◽  
Cell Densities

AbstractThe retinal pigment epithelium (RPE) of the quokka wallaby, Setonix brachyurus, grows and changes throughout life. To investigate factors that determine changes in the quokka RPE, we have examined topography of this tissue in experimentally enlarged eyes. Unilateral eyelid suture was conducted at the time of normal eye opening, postnatal day (P) 110, and animals were examined at 1 or 1½ years of age. The numbers and densities of RPE cells and the extent of multinucleation were compared with those in normal animals. Eyelid suture resulted in a 9.8% and 17.4% increase in retinal area at 1 and 1½ years, respectively; a significant degree of myopia was associated with this enlargement. Cell density topography in experimental eyes was not the same as in controls. Cells from central retina were disproportionately larger in the experimental than control eyes. However, the RPE cell topography in sutured eyes was not the same as that of aged retinae of a similar size. Notably, in sutured eyes there was no development of the high or highest cell densities seen in equatorial and temporal central RPE in aged retinae, respectively. Furthermore, the degree of cell enlargement in peripheral regions was slight compared with that observed in similar-sized, aged retinae. There was no increase in RPE cell number; rather, average cell area increased accompanied by no change or a slight decrease in RPE thickness. Consequently, overall volume of cells did not change significantly. The large number of multinucleate cells normally seen in aged animals was not observed in experimentally enlarged eyes, implying that an increase in cell volume may be the trigger for multinucleation.

scholarly journals Mechanism of CK2.3, a Novel Mimetic Peptide of Bone Morphogenetic Protein Receptor Type IA, Mediated Osteogenesis

2019 ◽  
Vol 20 (10) ◽  
pp. 2500 ◽  
Author(s):  
Vrathasha Vrathasha ◽  
Hilary Weidner ◽  
Anja Nohe
Keyword(s):  
Signaling Pathways ◽  
Treatment Options ◽  
Time Frame ◽  
Bmp Signaling ◽  
C2c12 Cells ◽  
Molecular Sequence ◽  
Sequence Of Events ◽  
Protein Receptor

Background: Osteoporosis is a degenerative skeletal disease with a limited number of treatment options. CK2.3, a novel peptide, may be a potential therapeutic. It induces osteogenesis and bone formation in vitro and in vivo by acting downstream of BMPRIA through releasing CK2 from the receptor. However, the detailed signaling pathways, the time frame of signaling, and genes activated remain largely unknown. Methods: Using a newly developed fluorescent CK2.3 analog, specific inhibitors for the BMP signaling pathways, Western blot, and RT-qPCR, we determined the mechanism of CK2.3 in C2C12 cells. We then confirmed the results in primary BMSCs. Results: Using these methods, we showed that CK2.3 stimulation activated OSX, ALP, and OCN. CK2.3 stimulation induced time dependent release of CK2β from BMPRIA and concurrently CK2.3 colocalized with CK2α. Furthermore, CK2.3 induced BMP signaling depends on ERK1/2 and Smad1/5/8 signaling pathways. Conclusion: CK2.3 is a novel peptide that drives osteogenesis, and we detailed the molecular sequence of events that are triggered from the stimulation of CK2.3 until the induction of mineralization. This knowledge can be applied in the development of future therapeutics for osteoporosis.

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