Pax6 dosage requirements in iris and ciliary body differentiation

Davis, N S; Yoffe, Chen; Raviv, S.; Antes, Ran; Berger, Joachim; Holzmann, Silvia; Stoykova, Anastassia; Overbeek, Paul A.; Tamm, Ernst R.; Ashery‐Padan, Ruth

doi:10.1016/j.ydbio.2009.06.023

Cited by 61 publications

(82 citation statements)

References 56 publications

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“…Although BMP signaling, Pax6, and Otx1 have recently been shown to be required for CB morphogenesis (17,18,20), it remains unclear how they work together to control CB morphogenesis at the molecular and cellular levels. In this study, we show that Notch2 signaling in the OCE drives CB morphogenesis at least in part by maintaining BMP signaling and promoting cell proliferation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Although Otx1 and Pax6 have been shown to be important for CB morphogenesis (18,20), their protein expression in the P0 Notch2 mutant OCE remains unchanged in comparison with the P0 control OCE, suggesting that Notch2 signaling must regulate other pathways to control CB morphogenesis (Fig. S5).…”

Section: D) (E-h)mentioning

confidence: 99%

“…Through conditional knockout (CKO), Dicer1, which encodes the key enzyme in the microRNA pathway, has recently been shown to be required for CB fate specification (15). The bone morphogenetic protein (BMP) signaling pathway and transcription factors orthodenticle homeobox 1 (Otx1) and paired box 6 (Pax6) are critical for CB morphogenesis (16)(17)(18)(19)(20). BMP4 and BMP7 are expressed in both ICE and OCE of the CB, and disruption of BMP signaling leads to severe CB morphogenesis defects (10,17,21,22).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: D) (E-h)mentioning

confidence: 99%

mentioning

confidence: 99%

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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 transgenic mouse lines Tyrp2-Cre, Z/AP, -Cre, Pou4f3-Cre and Dicer1 loxP/loxP were established as described previously (Davis et al, 2009;Lobe et al, 1999;Marquardt et al, 2001;Sage et al, 2006;Harfe et al, 2005) and Z/AP mouse lines were established as described previously (Davis et al, 2009;Lobe et al, 1999;Marquardt et al, 2001;Sage et al, 2006). Genotyping was performed by PCR using the primers listed in Table S1 in the supplementary material.…”

Section: Micementioning

confidence: 99%

Roles for Dicer1 in the patterning and differentiation of the optic cup neuroepithelium

2011

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SUMMARYThe embryonic ocular neuroepithilium generates a myriad of cell types, including the neuroretina, the pigmented epithelium, the ciliary and iris epithelia, and the iris smooth muscles. As in other regions of the developing nervous system, the generation of these various cell types requires a coordinated sequence of patterning, specification and differentiation events. We investigated the roles of microRNAs (miRNAs) in the development of optic cup (OC)-derived structures. We inactivated Dicer1, a key mediator of miRNA biosynthesis, within the OC in overlapping yet distinct spatiotemporal patterns. Ablation of Dicer1 in the inner layer of the OC resulted in patterning alteration, particularly at the most distal margins. Following loss of Dicer1, this region generated a cryptic population of cells with a mixed phenotype of neuronal and ciliary body (CB) progenitors. Notably, inactivation of Dicer1 in the retinal progenitors further resulted in abrogated neurogenesis, with prolongation of ganglion cell birth and arrested differentiation of other neuronal subtypes, including amacrine and photoreceptor cells. These alterations were accompanied by changes in the expression of Notch and Hedgehog signaling components, indicating the sensitivity of the pathways to miRNA activity. Moreover, this study revealed the requirement of miRNAs for morphogenesis of the iris and for the regulation of CB cell type proliferation and differentiation. Together, analysis of the three genetic models revealed novel, stage-dependent roles for miRNAs in the development of the ocular sub-organs, which are all essential for normal vision.

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“…For example, Pax6 deletion results in the absence of eyes; however, Pax6 haploinsufficiency leads to defects in the anterior segment of the eye that results in small eye in mice and aniridia in humans (Davis et al, 2009;Davis-Silberman et al, 2005;Schedl et al, 1996). Similarly, functional inactivation of Six3 in mice results in the absence of the forebrain and eyes, whereas removal of one allele leads to defects in the specification of the ventral telencephalon, and sometimes causes semilobar HPE Lagutin et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Six3 dosage mediates the pathogenesis of holoprosencephaly

et al. 2016

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Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic Six3 allele, we demonstrate in mice that variability in Six3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm. Consistent with these results, in vivo activation of the Shh signaling pathway rescued the semilobar phenotype but not the alobar phenotype. Our findings show that variations in Six3 dosage result in different forms of HPE.

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Pax6 dosage requirements in iris and ciliary body differentiation

Cited by 61 publications

References 56 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

Roles for Dicer1 in the patterning and differentiation of the optic cup neuroepithelium

Six3 dosage mediates the pathogenesis of holoprosencephaly

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