ArticleHuman molecular genetics2012
Pax2 regulates a fadd-dependent molecular switch that drives tissue fusion during eye development.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 40 citations in OpenAlex.
- Chemical screen in zebrafish lateral line identified compounds that ameliorate neomycin-induced ototoxicity by inhibiting ferroptosis pathway.Cell & bioscience · 2024Article
- BMP3 is a novel locus involved in the causality of ocular coloboma.Human genetics · 2022Article
- Pax2a, but not pax2b, influences cell survival and periocular mesenchyme localization to facilitate zebrafish optic fissure closure.Developmental dynamics : an official publication of the American Association of Anatomists · 2022Article
- Semper's cells in the insect compound eye: Insights into ocular form and function.Developmental biology · 2021Review
- Multiple roles for Pax2 in the embryonic mouse eye.Developmental biology · 2021Article
- dnmt1 function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye.Scientific reports · 2020Article
- Hyaloid vasculature and mmp2 activity play a role during optic fissure fusion in zebrafish.Scientific reports · 2020Article
- Mutation in Bmpr1b Leads to Optic Disc Coloboma and Ventral Retinal Gliosis in Mice.Investigative ophthalmology & visual science · 2020Article
- Review
- Review
- An update on the genetics of ocular coloboma.Human genetics · 2019Review
- Zebrafish mab21l2 mutants possess severe defects in optic cup morphogenesis, lens and cornea development.Developmental dynamics : an official publication of the American Association of Anatomists · 2019Article
- The zebrafish eye-a paradigm for investigating human ocular genetics.Eye (London, England) · 2017Review
- Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis.JCI insight · 2016Article
- Priorities and trends in the study of proteins in eye research, 1924-2014.Proteomics. Clinical applications · 2015Article
- Negative and positive auto-regulation of BMP expression in early eye development.Developmental biology · 2015Article
- Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma.Birth defects research. Part C, Embryo today : reviews · 2015Review
- Mutations in MAB21L2 result in ocular Coloboma, microcornea and cataracts.PLoS genetics · 2015Article
- Mutation of SALL2 causes recessive ocular coloboma in humans and mice.Human molecular genetics · 2014Article
- Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish.Cell death and differentiation · 2014Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
Tissue fusion is an essential morphogenetic mechanism in development, playing a fundamental role in developing neural tube, palate and the optic fissure. Disruption of genes associated with the tissue fusion can lead to congenital malformations, such as spina bifida, cleft lip/palate and ocular coloboma. For instance, the Pax2 transcription factor is required for optic fissure closure, although the mechanism of Pax2 action leading to tissue fusion remains elusive. This lack of information defining how transcription factors drive tissue morphogenesis at the cellular level is hampering new treatments options. Through loss- and gain-of-function analysis, we now establish that pax2 in combination with vax2 directly regulate the fas-associated death domain (fadd) gene. In the presence of fadd, cell proliferation is restricted in the developing eye through a caspase-dependent pathway. However, the loss of fadd results in a proliferation defect and concomitant activation of the necroptosis pathway through RIP1/RIP3 activity, leading to an abnormal open fissure. Inhibition of RIP1 with the small molecule drug necrostatin-1 rescues the pax2 eye fusion defect, thereby overcoming the underlying genetic defect. Thus, fadd has an essential physiological function in protecting the developing optic fissure neuroepithelium from RIP3-dependent necroptosis. This study demonstrates the molecular hierarchies that regulate a cellular switch between proliferation and the apoptotic and necroptotic cell death pathways, which in combination drive tissue morphogenesis. Furthermore, our data suggest that future therapeutic strategies may be based on small molecule drugs that can bypass the gene defects causing common congenital tissue fusion defects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.