Indian hedgehog signaling from endothelial cells is required for sclera and retinal pigment epithelium development in the mouse eye

Dakubo, Gabriel D.; Mazerolle, Chantal; Furimsky, Marosh; Yu, Chuan; St-Jacques, Benoit; McMahon, Andrew P.; Wallace, Valerie A.

doi:10.1016/j.ydbio.2008.05.528

Cited by 54 publications

(57 citation statements)

References 80 publications

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“…However, some previous studies are consistent with our finding that Ihh levels influence ocular development. For example, overexpression of murine Ihh in zebrafish embryos caused expansion of pax2 expression in the optic stalk (Hammerschmidt et al, 1996), and in the mouse, Ihh was shown to be required for proper development of the RPE and peri-ocular tissues (Dakubo et al, 2008). Interestingly, although we observed a significant elevation (approximately 4-fold) of ihhb expression at 8-12 hpf in sox4 morphants, this increase was even more pronounced at 18 and 24 hpf (approximately 15-fold).…”

Section: Discussionmentioning

confidence: 99%

Sox4 regulates choroid fissure closure by limiting Hedgehog signaling during ocular morphogenesis

Wen

Pillai-Kastoori

Wilson

et al. 2015

Developmental Biology

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SoxC transcription factors play critical roles in many developmental processes, including neurogenesis, cardiac formation, and skeletal differentiation. In vitro and in vivo loss-of-function studies have suggested that SoxC genes are required for oculogenesis, however the mechanism was poorly understood. Here, we have explored the function of the SoxC factor Sox4 during zebrafish eye development. We show that sox4a and sox4b are expressed in the forebrain and periocular mesenchyme adjacent to the optic stalk during early eye development. Knockdown of sox4 in zebrafish resulted in coloboma, a structural malformation of the eye that is a significant cause of pediatric visual impairment in humans, in which the choroid fissure fails to close. Sox4 morphants displayed altered proximo-distal patterning of the optic vesicle, including expanded pax2 expression in the optic stalk, as well as ectopic cell proliferation in the retina. We show that the abnormal ocular morphogenesis observed in Sox4-deficient zebrafish is caused by elevated Hedgehog (Hh) signaling, and this is due to increased expression of the Hh pathway ligand Indian hedgehog b (ihhb). Consistent with these results, coloboma in sox4 morphants could be rescued by pharmacological treatment with the Hh inhibitor cyclopamine, or by co-knockdown of ihhb. Conversely, overexpression of sox4 reduced Hh signaling and ihhb expression, resulting in cyclopia. Finally, we demonstrate that sox4 and sox11 have overlapping, but not completely redundant, functions in regulating ocular morphogenesis. Taken together, our data demonstrate that Sox4 is required to limit the extent of Hh signaling during eye development, and suggest that mutations in SoxC factors could contribute to the development of coloboma.

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Section: Discussionmentioning

confidence: 99%

Sox4 regulates choroid fissure closure by limiting Hedgehog signaling during ocular morphogenesis

Wen

Pillai-Kastoori

Wilson

et al. 2015

Developmental Biology

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“…We observed a substantial reduction in the expression of Ihh [which is expressed in choroid (Dakubo et al, 2008)] at P0.5 (5.2-fold) and P6.5 (3.3-fold), Ptch2 (2.2-times less at P0.5 and 2.3-times less at P6.5), Wnt3a (1.5-times less at P6.5) and Sfrp5 (2-times less at P0.5). The expression of two Notch pathway genes, Hes1 and Dll1, was also more than halved at P0.5 and P6.5, whereas Fzd5 expression was increased by 2.3-fold at P0.5.…”

Section: Altered Expression Of Selected Signaling Genes In Mutant Rpementioning

confidence: 92%

Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis

et al. 2013

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SUMMARYDysfunction or death of photoreceptors is the primary cause of vision loss in retinal and macular degenerative diseases. As photoreceptors have an intimate relationship with the retinal pigment epithelium (RPE) for exchange of macromolecules, removal of shed membrane discs and retinoid recycling, an improved understanding of the development of the photoreceptor-RPE complex will allow better design of gene-and cell-based therapies. To explore the epigenetic contribution to retinal development we generated conditional knockout alleles of DNA methyltransferase 1 (Dnmt1) in mice. Conditional Dnmt1 knockdown in early eye development mediated by Rx-Cre did not produce lamination or cell fate defects, except in cones; however, the photoreceptors completely lacked outer segments despite near normal expression of phototransduction and cilia genes. We also identified disruption of RPE morphology and polarization as early as E15.5. Defects in outer segment biogenesis were evident with Dnmt1 exon excision only in RPE, but not when excision was directed exclusively to photoreceptors. We detected a reduction in DNA methylation of LINE1 elements (a measure of global DNA methylation) in developing mutant RPE as compared with neural retina, and of Tuba3a, which exhibited dramatically increased expression in mutant retina. These results demonstrate a unique function of DNMT1-mediated DNA methylation in controlling RPE apicobasal polarity and neural retina differentiation. We also establish a model to study the epigenetic mechanisms and signaling pathways that guide the modulation of photoreceptor outer segment morphogenesis by RPE during retinal development and disease.

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“…Eye development not only depends on SHH, but also on the related morphogen indian hedgehog (IHH) produced by the choroid adjacent to the RPE (Dakubo et al, 2008). Expression of Ihh in the choroid was unchanged in Lrp2 À/À mice (Figure S3B).…”

Section: Lrp2 Deficiency Causes Ectopic Induction Of Shh Signals In Tmentioning

confidence: 99%

LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli

et al. 2015

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During forebrain development, LRP2 promotes morphogen signaling as an auxiliary SHH receptor. However, in the developing retina, LRP2 assumes the opposing function, mediating endocytic clearance of SHH and antagonizing morphogen action. LRP2-mediated clearance prevents spread of SHH activity from the central retina into the retinal margin to protect quiescent progenitor cells in this niche from mitogenic stimuli. Loss of LRP2 in mice increases the sensitivity of the retinal margin for SHH, causing expansion of the retinal progenitor cell pool and hyperproliferation of this tissue. Our findings document the ability of LRP2 to act, in a context-dependent manner, as activator or inhibitor of the SHH pathway. Our current findings uncovered LRP2 activity as the molecular mechanism imposing quiescence of the retinal margin in the mammalian eye and suggest SHH-induced proliferation of the retinal margin as cause of the large eye phenotype observed in mouse models and patients with LRP2 defects.

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Indian hedgehog signaling from endothelial cells is required for sclera and retinal pigment epithelium development in the mouse eye

Cited by 54 publications

References 80 publications

Sox4 regulates choroid fissure closure by limiting Hedgehog signaling during ocular morphogenesis

Sox4 regulates choroid fissure closure by limiting Hedgehog signaling during ocular morphogenesis

Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis

LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli

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