Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

Lahrouchi, Najim; George, Aman; Ratbi, Ilham; Schneider, Ronen; Elalaoui, Siham Chafai; Moosa, Shahida; Bharti, Sanita; Sharma, Ruchi; Abu‐Asab, Mones; Onojafe, Felix; Adadi, Najlae; Lodder, Elisabeth M.; Laarabi, Fatima Zahra; Lamsyah, Yassine; Elorch, H; Chebbar, Imane; Postma, Alex V.; Lougaris, Vassilios; Plebani, Alessandro; Altmueller, Janine; Kyrieleis, Henriette; Meiner, Vardiella; McNeill, Helen; Bharti, Kapil; Lyonnet, Stanislas; Wollnik, Bernd; Henrion‐Caude, Alexandra; Berraho, A.; Hildebrandt, Friedhelm; Bezzina, Connie R.; Brooks, Brian P.; Sefiani, Abdelaziz

doi:10.1038/s41467-019-08547-w

Cited by 28 publications

(41 citation statements)

References 35 publications

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“…Recent work from our lab has characterized the composition of core BM components within the fissure 23 . Additionally, work from other labs has identified several molecular components associated with cell-cell adhesion and epithelial sheet fusion to function within the fissure, including β-catenin, n-cadherin, and netrin 22,24,[48][49][50][51] . However, the timing and the molecular mechanism organizing and regulating these components remains uncharacterized.…”

Section: Discussionmentioning

confidence: 99%

Hyaloid vasculature and mmp2 activity play a role during optic fissure fusion in zebrafish

Weaver

Piedade

Meshram

et al. 2020

Sci Rep

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Vertebrate retinal development requires timely and precise fusion of the optic fissure (OF). Failure of this event leads to congenital vision impairment in the form of coloboma. Recent studies have suggested hyaloid vasculature to be involved in OF fusion. In order to examine this link, we analyzed OF fusion and hyaloid vasculogenesis in the zebrafish pax2a noi mutant line. We first determined that pax2a −/− embryos fail to accumulate F-actin in the OF prior to basement membrane (BM) degradation. Furthermore, using 3D and live imaging we observed reduced OF hyaloid vascularization in pax2a −/− embryos. When examining the connection between pax2a loss of function and hyaloid vasculature, we observed significant reduction of talin1 expression, a regulator of hyaloid vasculature. In addition, cranial VEGF expression was found to be reduced in pax2a −/− embryos. Pharmacological inhibition of VEGF signaling phenocopied the pax2a −/− vasculature, F-actin and BM degradation phenotypes. Lastly, we determined that OF associated hyaloid vasculature is a source of mmp2, mmp14a and mmp14b expression and showed that mmp2 is functionally necessary for degradation of OF BM. Taken together we propose a pax2a driven mechanism that ensures proper and timely hyaloid vasculature invasion of the OF in order to facilitate availability of the BM remodeler mmp2. Ocular development is a highly conserved process amongst vertebrate species. Assembly of the hemispherical, retinal structure from an initially flat sheet of cells requires many complex morphogenetic movements. One such morphogenetic movement involves the invagination of the optic vesicle which results in a fissure forming at the ventral region of the developing retina. This fissure, known as the choroid or optic fissure (OF), enables hyaloid vasculature cell migration into the developing retina and subsequent establishment of the hyaloid vasculature. Hyaloid vasculature is a temporary circulatory system required for ocular development, and in most cases will degenerate once mature blood vessels begin to grow 1-4. As soon as the hyaloid vasculature has been established, the two opposing retinal epithelial sheets of the OF will undergo fusion. Thereby, they encase the ganglion cell axons localized in the optic stalk and complete retinal morphogenesis. Failure of OF fusion leads to a congenital blinding disorder known as coloboma 5-7. Coloboma is a prevalent cause of pediatric blindness, accounting for approximately 10% of cases worldwide 6,8. This makes it one of the leading causes of pediatric blindness. Coloboma is a spectrum disorder presenting unilaterally or bilaterally and ranging in severity from minor visual impairment, to complete blindness in the affected eye 9. This spectrum of severity is associated with the location and degree to which the OF was able to fuse and the severity of subsequent loss of ganglion cell axons 7. Coloboma has been studied for many decades in many different species. Work over this time has led to a general outline of the signaling and morphogen...

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Section: Discussionmentioning

confidence: 99%

Hyaloid vasculature and mmp2 activity play a role during optic fissure fusion in zebrafish

Weaver

Piedade

Meshram

et al. 2020

Sci Rep

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“…The latter involves changes in cell polarity [22] and adjustment of cell-cell contacts. Among potentially many factors, FAT1, an atypical protocadherin, was found to be important for fusion [43]. In addition to these structural changes, a tight control of cell proliferation and cell death seems to be important to prevent coloboma [44][45][46].…”

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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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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“…Hippo pathway components have been recently identified as genes with clinical relevance for coloboma (23,53,54,64). Heterozygous loss of function mutations in YAP1 were identified in 2 unrelated families exhibiting coloboma (3).…”

Section: Role Of Hippo Signaling In Of Closure In Humansmentioning

confidence: 99%

“…In humans, a subpopulation of colobomata is a result of mutations in developmentally important genes, however, the origins for many OF closure defects are unknown (for reviews, see (3,7,8,13,14)). Additional genes have been identified in animal models; substantial progress has been made in understanding critical processes, including growth and patterning of the ventral optic cup and optic nerve head (15- 19), cell-cell contact and signaling (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), crosstalk with migrating hyaloid precursors and extracellular matrix components (31)(32)(33)(34)(35)(36), cytoskeleton dynamics (37,38), epigenetics (39), degradation of ECM and cellular proteins (40)(41)(42), programmed cell death, survival and cell proliferation (43,44) (for reviews, see (7,8,13)). 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).…”

Section: Introductionmentioning

confidence: 99%

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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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Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

Cited by 28 publications

References 35 publications

Hyaloid vasculature and mmp2 activity play a role during optic fissure fusion in zebrafish

Hyaloid vasculature and mmp2 activity play a role during optic fissure fusion in zebrafish

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

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

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