Journal Article

Pax2 regulates a <i>fadd</i>-dependent molecular switch that drives tissue fusion during eye development

Ishaq A. Viringipurampeer, Todd Ferreira, Shannon DeMaria, Jookyung J. Yoon, Xianghong Shan, Mariya Moosajee, Kevin Gregory-Evans, John Ngai and Cheryl Y. Gregory-Evans

in Human Molecular Genetics

Volume 21, issue 10, pages 2357-2369
Published in print May 2012 | ISSN: 0964-6906
Published online February 2012 | e-ISSN: 1460-2083 | DOI:
Pax2 regulates a fadd-dependent molecular switch that drives tissue fusion during eye development

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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.

Journal Article.  7920 words.  Illustrated.

Subjects: Genetics and Genomics

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