Transcriptome profiling of zebrafish optic fissure fusion

Richardson, Rose; Owen, Nicholas; Toms, Maria; Young, Rodrigo; Tracey‐White, Dhani; Moosajee, Mariya

doi:10.1038/s41598-018-38379-5

Cited by 24 publications

(48 citation statements)

References 41 publications

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“…These factors could be derived from either the POM cells or the fissure margin cells. Findings from recent transcriptional analyses likely include potential candidates [18,32,35,62].…”

Section: Late Bmp Induction Results In Only Subtle Direct Changes Of mentioning

confidence: 99%

“…Furthermore, TGFβ was found important for basal lamina degradation [18]. Even though many factors were linked to the degradation of the basal lamina and recent transcriptional analyses include potential effector molecules [18,32,35], such factors need further analysis and validation. Besides, it is also not clear whether the POM and the NR/RPE precursors cooperate during basal lamina degradation.…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Analysis of Optic Fissure Fusion in Zebrafish: Pioneer Cells, Basal Lamina, Hyaloid Vessels, and How Fissure Fusion is Affected by BMP

Eckert

Knickmeyer

Heermann

2020

IJMS

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Colobomata, persistent optic fissures, frequently cause congenital blindness. Here, we focused on optic fissure fusion using in vivo time-lapse imaging in zebrafish. We identified the fusion initiating cells, which we termed “pioneer cells.” Based on morphology, localization, and downregulation of the neuroretinal (NR) precursor marker rx2, these cells could be considered as retinal pigment epithelial (RPE) progenitors. Notably, pioneer cells regain rx2 expression and integrate into the NR after fusion, indicating that they do not belong to the pool of RPE progenitors, supported by the lack of RPE marker expression in pioneer cells. They establish the first cellular contact between the margins in the proximal fissure region and separate the hyaloid artery and vein. After initiation, the fusion site is progressing distally, increasing the distance between the hyaloid artery and vein. A timed BMP (Bone Morphogenetic Protein) induction, resulting in coloboma, did not alter the morphology of the fissure margins, but it did affect the expression of NR and RPE markers within the margins. In addition, it resulted in a persisting basal lamina and persisting remnants of periocular mesenchyme and hyaloid vasculature within the fissure, supporting the necessity of BMP antagonism within the fissure margins. The hampered fissure fusion had severe effects on the vasculature of the eye.

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“…These factors could be derived from either the POM cells or the fissure margin cells. Findings from recent transcriptional analyses likely include potential candidates [18,32,35,62].…”

Section: Late Bmp Induction Results In Only Subtle Direct Changes Of mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vivo Analysis of Optic Fissure Fusion in Zebrafish: Pioneer Cells, Basal Lamina, Hyaloid Vessels, and How Fissure Fusion is Affected by BMP

Eckert

Knickmeyer

Heermann

2020

IJMS

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“…Finally, the elephant in the room has always been the identity of the BM remodeling mechanism. To date, only adamts16 has been functionally examined in context of fissure fusion, mmp2 activity was detected during mouse OF fusion and mmp23bb was implicated in the fusion process from transcriptomic data (41, 50, 52).…”

Section: Discussionmentioning

confidence: 99%

“…We have not been able to reproduce adamts16 expression within the fissure. Recent studies in mice, zebrafish and chick have compared expression in OF cells pre, during and post fusion (24, 50, 58, 59). Surprisingly, none of these studies identified any obvious candidates for carrying out BM remodeling, including mmp2 and mmp14.…”

Section: Discussionmentioning

confidence: 99%

Pax2a regulates angiogenesis to facilitate mmp2-dependent basement membrane remodeling of the optic fissure

Weaver

Piedade

Meshram

et al. 2019

Preprint

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Vertebrate retinal development requires timely and precise fusion of the optic fissure (OF). Recent studies have suggested hyaloid vasculature to be involved in optic fissure fusion. In order to examine this link, we analyzed OF fusion and hyaloid vasculogenesis in the zebrafish pax2anoi mutant line. We determined that OF basement membrane (BM) remodeling, normally preceded by F-actin accumulation is mis-regulated in pax2a−/− embryos. Comparing transcriptomic profiles of pax2a−/− and wildtype eyes we discovered a novel connection between regulation of angiogenesis and fusion. Pax2a−/− eyes exhibited a significant reduction of talin1 expression, a regulator of hyaloid vasculature, in addition to increased expression of an anti-angiogenic protease, adamts1. Using 3D and live imaging we observed reduced OF hyaloid vascularization in pax2a−/− embryos. Additionally, pharmacological inhibition of VEGF signaling or adamts1 mRNA overexpression phenocopied the pax2a−/− vasculature, F-actin and BM remodeling phenotypes. Finally, we show that hyaloid vasculature expresses mmp2 which is necessary for remodeling the fissure BM. Taken together we propose a pax2a driven mechanism that restricts anti-angiogenic activity of adamts1 enabling hyaloid vasculature invasion of the OF and delivery of the BM remodeler mmp2.

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“…Elegant in vivo imaging studies in zebrafish and excellent anatomical analyses in chick have characterized important morphogenetic and cellular behavior (20,27,34,(45)(46)(47)(48)(49). In addition, comprehensive gene expression analyses have identified novel candidate genes potentially relevant for regulating OF closure (27,47,(50)(51)(52).…”

Section: Introductionmentioning

confidence: 99%

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye

Sun

Ramirez

Spiller

et al. 2020

Preprint

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Uveal coloboma represents one of the most common congenital ocular malformations accounting for up to 10% of childhood blindness (1~ in 5,000 live birth). Coloboma originates from defective fusion of the optic fissure (OF), a transient gap that forms during eye morphogenesis by asymmetric, ventral invagination. Genetic heterogeneity combined with the activity of developmentally regulated genes suggest multiple mechanisms regulating OF closure. The tumor suppressor and FERM domain protein neurofibromin 2 (NF2) controls diverse processes in cancer, development and regeneration, via Hippo pathway and cytoskeleton regulation. In humans, NF2 mutations can cause ocular abnormalities, including coloboma, however, its actual role in OF closure is unknown. Using conditional inactivation in the embryonic mouse eye, our data indicates that loss of Nf2 function results in a novel underlying cause for coloboma. In particular, mutant eyes show substantially increased RPE proliferation in the fissure region with concomitant acquisition of RPE cell fate. Cells lining the OF margin can maintain RPE fate ectopically and fail to transition from neuroepithelial to cuboidal shape. In the dorsal RPE of the optic cup, Nf2 inactivation leads to a robust increase in cell number, with local disorganization of the cytoskeleton components F--actin and pMLC2. We propose that RPE hyperproliferation is the primary cause for the observed defects causing insufficient alignment of the OF margins in Nf2 mutants and failure to fuse properly, resulting in persistent coloboma. Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during optic fissure closure.

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Transcriptome profiling of zebrafish optic fissure fusion

Cited by 24 publications

References 41 publications

In Vivo Analysis of Optic Fissure Fusion in Zebrafish: Pioneer Cells, Basal Lamina, Hyaloid Vessels, and How Fissure Fusion is Affected by BMP

In Vivo Analysis of Optic Fissure Fusion in Zebrafish: Pioneer Cells, Basal Lamina, Hyaloid Vessels, and How Fissure Fusion is Affected by BMP

Pax2a regulates angiogenesis to facilitate mmp2-dependent basement membrane remodeling of the optic fissure

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye

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