A Zebrafish Model of Axenfeld-Rieger Syndrome Reveals That pitx2 Regulation by Retinoic Acid Is Essential for Ocular and Craniofacial Development

Bohnsack, Brenda L.; Kasprick, Daniel S.; Kish, Phillip E.; Goldman, Daniel; Kahana, Alon

doi:10.1167/iovs.11-8494

Cited by 59 publications

(103 citation statements)

References 74 publications

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“…In contrast to humans, eye and tooth phenotypes were only observed in homozygous pitx2HD −/− zebrafish. In previous work, transient knockdown of Pitx2 expression using morpholino oligonucleotides caused defects in eye, craniofacial and asymmetric brain development (Bohnsack et al, 2012; Garric et al, 2014; Liu and Semina, 2012). pitx2HD mutants developed eye phenotypes that were consistent with Pitx2 morpholino injected embryos, but did not develop other defects (e.g.…”

Section: Discussionmentioning

confidence: 97%

Mutations in zebrafish pitx2 model congenital malformations in Axenfeld-Rieger syndrome but do not disrupt left-right placement of visceral organs

Buel

Amack

2016

Developmental Biology

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Pitx2 is a conserved homeodomain transcription factor that has multiple functions during embryonic development. Mutations in human PITX2 cause autosomal dominant Axenfeld-Rieger syndrome (ARS), characterized by congenital eye and tooth malformations. Pitx2−/− knockout mouse models recapitulate aspects of ARS, but are embryonic lethal. To date, ARS treatments remain limited to managing individual symptoms due to an incomplete understanding of PITX2 function. In addition to regulating eye and tooth development, Pitx2 is a target of a conserved Nodal (TGFβ) signaling pathway that mediates left-right (LR) asymmetry of visceral organs. Based on its highly conserved asymmetric expression domain, the Nodal-Pitx2 axis has long been considered a common denominator of LR development in vertebrate embryos. However, functions of Pitx2 during asymmetric organ morphogenesis are not well understood. To gain new insight into Pitx2 function we used genome editing to create mutations in the zebrafish pitx2 gene. Mutations in the pitx2 homeodomain caused phenotypes reminiscent of ARS, including aberrant development of the cornea and anterior chamber of the eye and reduced or absent teeth. Intriguingly, LR asymmetric looping of the heart and gut was normal in pitx2 mutants. These results suggest conserved roles for Pitx2 in eye and tooth development and indicate Pitx2 is not required for asymmetric looping of zebrafish visceral organs. This work establishes zebrafish pitx2 mutants as a new animal model for investigating mechanisms underlying congenital malformations in ARS and high-throughput drug screening for ARS therapeutics. Additionally, pitx2 mutants present a unique opportunity to identify new genes involved in vertebrate LR patterning. We show Nodal signaling—independent of Pitx2—controls asymmetric expression of the fatty acid elongase elovl6 in zebrafish, pointing to a potential novel pathway during LR organogenesis.

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Section: Discussionmentioning

confidence: 97%

Mutations in zebrafish pitx2 model congenital malformations in Axenfeld-Rieger syndrome but do not disrupt left-right placement of visceral organs

Buel

Amack

2016

Developmental Biology

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“…25,28,29 One micromole of Ro41-5253 blocked all domains of gfp expression in Tg(12XRARE:GFP) larvae without negative effects on health (Supplemental Figure 2). Larvae treated with Ro41-5253 immediately after gentamicin injection had decreased survival (Figure 2A), indicating impaired functional recovery.…”

Section: Inhibition Of Ra Signaling In Zebrafish Larvaementioning

confidence: 96%

“…In addition to Pitt AB wild-type, embryos were used from the following published transgenic lines: Tg(12XRARE-ef1a: EGFP) s72 , 28 and Tg(PT:EGFP). 22 In addition, the Tg(cdh17:mCherry) line was used, which was generated in conjunction with and displays pronephric mCherry expression analogous to Tg(cdh17:EGFP).…”

Section: Zebrafish Studies Zebrafish Husbandrymentioning

confidence: 99%

Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI

Chiba¹,

Skrypnyk²,

Skvarca

et al. 2016

Journal of the American Society of Nephrology

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Retinoic acid (RA) has been used therapeutically to reduce injury and fibrosis in models of AKI, but little is known about the regulation of this pathway and what role it has in regulating injury and repair after AKI. In these studies, we show that RA signaling is activated in mouse and zebrafish models of AKI, and that these responses limit the extent of injury and promote normal repair. These effects were mediated through a novel mechanism by which RA signaling coordinated the dynamic equilibrium of inflammatory M1 spectrum versus alternatively activated M2 spectrum macrophages. Our data suggest that locally synthesized RA represses proinflammatory macrophages, thereby reducing macrophage-dependent injury post-AKI, and activates RA signaling in injured tubular epithelium, which in turn promotes alternatively activated M2 spectrum macrophages. Because RA signaling has an essential role in kidney development but is repressed in the adult, these findings provide evidence of an embryonic signaling pathway that is reactivated after AKI and involved in reducing injury and enhancing repair.

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“…We and others have shown that zebrafish can serve as robust direct models for craniofacial abnormalities observed in humans. 39,42,[48][49][50][51][52] We assessed the craniofacial patterning by measuring the angle of ceratohyal (CH) cartilage in ventral images acquired from 3 dpf larvae. We observed a significant increase of the CH angle in bptf CRISPR F0 mutants (102 versus 91 for F0 mutants versus controls; p % 0.0001, n ¼ 47-59 larvae/batch, repeated; Figure 2).…”

Section: Bptf F0 Mutants Display Abnormal Craniofacial Patterningmentioning

confidence: 99%

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

Stankiewicz

Khan

Szafrański

et al. 2017

The American Journal of Human Genetics

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Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

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A Zebrafish Model of Axenfeld-Rieger Syndrome Reveals That pitx2 Regulation by Retinoic Acid Is Essential for Ocular and Craniofacial Development

Cited by 59 publications

References 74 publications

Mutations in zebrafish pitx2 model congenital malformations in Axenfeld-Rieger syndrome but do not disrupt left-right placement of visceral organs

Mutations in zebrafish pitx2 model congenital malformations in Axenfeld-Rieger syndrome but do not disrupt left-right placement of visceral organs

Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

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