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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.

ABSTRACT: The homeobox transcription factor PITX2 is a known regulator of mammalian ocular development, and human PITX2 mutations are associated with Axenfeld-Rieger syndrome (ARS). However, the treatment of patients with ARS remains mostly supportive and palliative.The authors used molecular genetic, pharmacologic, and embryologic techniques to study the biology of ARS in a zebrafish model that uses transgenes to mark neural crest and muscle cells in the head.The authors demonstrated in vivo that pitx2 is a key downstream target of retinoic acid (RA) in craniofacial development, and this pathway is required for coordinating neural crest, mesoderm, and ocular development. pitx2a knockdown using morpholino oligonucleotides disrupts jaw and pharyngeal arch formation and recapitulates ocular characteristics of ARS, including corneal and iris stroma maldevelopment. These phenotypes could be rescued with human PITX2A mRNA, demonstrating the specificity of the knockdown and evolutionary conservation of pitx2a function. Expression of the ARS dominant negative human PITX2A K50E allele also caused ARS-like phenotypes. Similarly, inhibition of RA synthesis in the developing eye (genetic or pharmacologic) disrupted craniofacial and ocular development, and human PITX2A mRNA partially rescued these defects.RA regulation of pitx2 is essential for coordinating interactions among neural crest, mesoderm, and developing eye. The marked evolutionary conservation of Pitx2 function in eye and craniofacial development makes zebrafish a potentially powerful model of ARS, amenable to in vivo experimentation and development of potential therapies.

SUBMITTER: Bohnsack BL

PROVIDER: S-EPMC3292384 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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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.

Bohnsack Brenda L BL Kasprick Daniel S DS Kish Phillip E PE Goldman Daniel D Kahana Alon A

Investigative ophthalmology & visual science 20120103 1

<h4>Purpose</h4>The homeobox transcription factor PITX2 is a known regulator of mammalian ocular development, and human PITX2 mutations are associated with Axenfeld-Rieger syndrome (ARS). However, the treatment of patients with ARS remains mostly supportive and palliative.<h4>Methods</h4>The authors used molecular genetic, pharmacologic, and embryologic techniques to study the biology of ARS in a zebrafish model that uses transgenes to mark neural crest and muscle cells in the head.<h4>Results</ ...[more]

PMID: 22125274

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Project description:Purpose:To identify the genetic cause in a four-generation Chinese family with Axenfeld-Rieger syndrome (ARS). Methods:The family members received clinical examinations of the eye, tooth, periumbilical skin, and heart. Sanger sequencing and whole-exome sequencing (WES) were performed to screen potential mutations. The genomic deletion region around the PITX2 gene was estimated from single nucleotide polymorphism (SNP) data from WES and then confirmed with "quantitative PCR (qPCR) using a set of primers. The DNA breakpoint was further identified with long-range PCR and Sanger sequencing. Results:Symptoms including anterior segment dysplasia of the eye (iris dysplasia, multiple pupils, and posterior embryotoxon), dental dysplasia, and periumbilical skin redundancy were present in all of the affected individuals. Three of them had glaucoma. Corneal abnormalities (inferior sclerocornea, corneal endothelial dystrophy, and central corneal scar) were seen in most of the affected individuals. Cataract, limited eye movement, electrocardiographic abnormalities, intellectual disability, and recurrent miscarriages were observed in some of the affected individuals. No mutations in the coding and exon-intron adjacent regions of the PITX2 and FOXC1 genes were identified with Sanger sequencing. According to the SNP data from WES, we suspected that there might be a deletion region (at most 1.6 Mb) around the PITX2 gene. With the use of qPCR and long-range PCR, we identified a 53,840 bp deletion (chr4: 111,535,454-111,588,933) spanning PITX2 and PANCR. The genomic deletion cosegregated with the major ARS symptoms observed in the family members. Conclusions:With the help of WES, qPCR, and long-range PCR, we identified a genomic deletion encompassing PITX2 and the adjacent noncoding gene PANCR in a Chinese family with ARS. The clinical features of the affected individuals are reported. This work may broaden understanding of the phenotypic and mutational spectrums related to ARS.

Dataset Information

A zebrafish model of axenfeld-rieger syndrome reveals that pitx2 regulation by retinoic acid is essential for ocular and craniofacial development.

Publications

A zebrafish model of axenfeld-rieger syndrome reveals that pitx2 regulation by retinoic acid is essential for ocular and craniofacial development.

Similar Datasets

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