Ventroptin: A BMP-4 Antagonist Expressed in a Double-Gradient Pattern in the Retina

Sakuta, Hiraki; Suzuki, Ryoko; Takahashi, Hiroo; Kato, Akira; Shintani, Takafumi; Iemura, Shun‐ichiro; Yamamoto, Takamasa; Ueno, Naoto; Noda, Masaharu

doi:10.1126/science.1058379

Cited by 188 publications

(177 citation statements)

References 20 publications

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“…4E). We have further shown that they indeed repress BMP signaling activities in human 293T cells when overexpressed, which is consistent with published results (46,47) (Fig. S6 B-H).…”

Section: Notch2 Represses the Expression Of Two Bmp Signaling Inhibitorsupporting

confidence: 93%

Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye

Zhou

Tanzie

Yan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The ciliary body (CB) of the mammalian eye is responsible for secreting aqueous humor to maintain intraocular pressure, which is elevated in the eyes of glaucoma patients. It contains a folded two-layered epithelial structure comprising the nonpigmented inner ciliary epithelium (ICE), the pigmented outer ciliary epithelium (OCE), and the underlying stroma. Although the CB has an important function in the eye, its morphogenesis remains poorly studied. In this study, we show that conditional inactivation of the Jagged 1 (Jag1)-Notch2 signaling pathway in the developing CB abolishes its morphogenesis. Notch2 is expressed in the OCE of the CB, whereas Jag1 is expressed in the ICE. Conditional inactivation of Jag1 in the ICE or Notch2 in the OCE disrupts CB morphogenesis, but neither affects the specification of the CB region. Notch2 signaling in the OCE is required for promoting cell proliferation and maintaining bone morphogenetic protein (BMP) signaling, both of which have been suggested to be important for CB morphogenesis. Although Notch and BMP signaling pathways are known to crosstalk via the interaction between their downstream transcriptional factors, this study suggests that Notch2 maintains BMP signaling in the OCE possibly by repressing expression of secreted BMP inhibitors. Based on our findings, we propose that Jag1-Notch2 signaling controls CB morphogenesis at least in part by regulating cell proliferation and BMP signaling.T he mammalian eye is composed of the anterior segment, the posterior retina and the vitreous. The anterior segment consists of cornea, lens, and ciliary body (CB), whereas the posterior retina contains six types of retinal neurons and Müller glial cells, which are organized into three distinct cell layers. The light passes through the cornea and is then focused by the lens and detected by photoreceptors in the retina. Both the aqueous humor anteriorly and the vitreous humor posteriorly function together to sustain intraocular pressure (IOP) in the eye and thereby maintain its shape. Pressure regulation is particularly important because abnormally high IOP is a major risk factor for glaucoma (1). In the eye, the CB is responsible for producing aqueous humor (2). Although high IOP is often attributed to the blockage of the drainage system for the vitreous, known as the trabecular meshwork, abnormal CB function might also contribute to high IOP formation because of excess aqueous humor production. Finally, contraction of the muscles in the CB controls lens accommodation for near versus far vision. Despite its important biological functions and potential medical significance, the formation and development of the CB remain poorly studied.The CB contains two layers of apically adhered epithelial sheets, the pigmented outer ciliary epithelium (OCE) and the nonpigmented inner ciliary epithelium (ICE), and the underlying stroma (2). It forms at the periphery of the developing optic cup and first segregates from the retina and then from the iris. One previous study suggested that blood vesse...

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“…4E). We have further shown that they indeed repress BMP signaling activities in human 293T cells when overexpressed, which is consistent with published results (46,47) (Fig. S6 B-H).…”

Section: Notch2 Represses the Expression Of Two Bmp Signaling Inhibitorsupporting

confidence: 93%

Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye

Zhou

Tanzie

Yan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Bmp signaling is essential for lens development and is involved in retinal differentiation (67)(68)(69)(70). Although a role for Bmps has been suggested in adult retinal pigment epithelium (71), little is known about Bmp and Smad pathways in the mature retinal photoreceptors.…”

Section: Discussionmentioning

confidence: 99%

Altered Expression of Genes of the Bmp/Smad and Wnt/Calcium Signaling Pathways in the Cone-only Nrl-/- Mouse Retina, Revealed by Gene Profiling Using Custom cDNA Microarrays

Yu¹,

He²,

Friedman³

et al. 2004

Journal of Biological Chemistry

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Many mammalian retinas are rod-dominant, and hence our knowledge of cone photoreceptor biology is relatively limited. To gain insights into the molecular differences between rods and cones, we compared the gene expression profile of the rod-dominated retina of wild type mouse with that of the cone-only retina of Nrl ؊/؊ (Neural retina leucine zipper knockout) mouse. Our analysis, using custom microarrays of eye-expressed genes, provided equivalent data using either direct or reference-based experimental designs, confirmed differential expression of rod-and cone-specific genes in the Nrl ؊/؊ retina and identified novel genes that could serve as candidates for retinopathies or for functional studies. In addition, we detected altered expression of several genes that encode cell signaling or structural proteins. Prompted by these findings, additional real-time PCR analysis revealed that genes belonging to the Bmp/Smad and Wnt/Ca 2؉ signaling pathways are expressed in the mature wild type retina and that their expression is significantly altered in the Nrl ؊/؊ retina. Chromatin immunoprecipitation analysis of adult retina identified Bmp4 and Smad4, which are down-regulated in the Nrl ؊/؊ retina, as possible direct transcriptional targets of Nrl. Consistent with these studies, Bmp4 and Smad4 are expressed in the mature rod photoreceptors of mouse retina. Modulation of Bmp4 and/or Smad4 by Nrl may provide a mechanism for integrating diverse cell signaling networks in rods. We hypothesize that Bmp/Smad and Wnt/Ca 2؉ pathways participate in cell-cell communication in the mature retina, and expression changes observed in the Nrl ؊/؊ retina reflect their biased utilization in rod versus cone homeostasis.

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“…The recent discovery that activated Smads can associate with the Drosha complex and regulate its activity suggests a possible mechanism by which this could occur. Given the known role of BMP/TGFbeta signaling in regulating various aspects of retinal development (Davis et al, 2000;Sakuta et al, 2001;Kim et al, 2005), this may be a possible mechanism of action for these factors that bears investigating.…”

Section: Regulated Processing Of Retinal Pri-mirnas?mentioning

confidence: 99%

New meaning in the message: Noncoding RNAs and their role in retinal development

Rapicavoli

Blackshaw

2009

Developmental Dynamics

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Recent studies have indicated that non-protein-coding RNAs (ncRNAs) may play prominent and diverse roles in the development of the nervous system. These ncRNAs are now known to perform a broad range of cellular functions, and in particular appear to be prominent players in the regulation of transcription and translation. In this review, we discuss recent advances in our understanding of the role of ncRNAs in vertebrate retinal development. Noncoding RNAs that are known or suspected to play a functional role in the specification and maturation of retinal cell subtypes include miRNAs, long noncoding opposite-strand transcripts (OSTs), and other long ncRNAs such as Tug1 and RNCR2. Though the mechanism of action of most of these ncRNAs is still largely unclear, it is likely that these molecules represent a major, and thus far largely unappreciated, component of the molecular machinery involved in retinal cell fate specification.

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Ventroptin: A BMP-4 Antagonist Expressed in a Double-Gradient Pattern in the Retina

Cited by 188 publications

References 20 publications

Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye

Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye

Altered Expression of Genes of the Bmp/Smad and Wnt/Calcium Signaling Pathways in the Cone-only Nrl-/- Mouse Retina, Revealed by Gene Profiling Using Custom cDNA Microarrays

New meaning in the message: Noncoding RNAs and their role in retinal development

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