The role of GRHL-3, a mammalian homologue of Drosophila grainyhead, in neural tube development

Funded Activity Summary

Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first few hours of life. These abnormalities occur frequently (1-1000 live births) and are a direct result of failure of the neural tube to close during embryogenesis. NTDs are influenced by both environmental and genetic factors. The best characterised environmental factor is the dietary supplement folate, which when administered before conception results in a reduction in the incidence of spina bifida. The genetic complexity is evidenced by the array of mouse genetic mutations that give rise to NTDs. One of these mouse mutations, known as Curly tail (ct), has served as the major animal model of human NTDs. This is because the ct mice are resistant to folate administration (like most of the cases of spina bifida currently seen in patients) and because the mice seem to have normal development in virtually all other organ systems. Ironically, the genetic mutation that causes the curly tail phenotype has remained undiscovered for over 50 years. We have now identified the gene mutated in the curly tail mice. This gene is highly conserved in humans suggesting that it will play a similar role in neural tube development in man. The gene, known as GRHL-3, is a descendant of a fly gene critical for development of the nervous system in that organism. The studies we propose here will examine the developmental pathways involved in normal neural tube closure in mice and humans and will impact on our understanding of these devastating congenital malformations.

Funded Activity Details

Start Date: 01-01-2004

End Date: 01-01-2006

Funding Scheme: NHMRC Project Grants

Funding Amount: $496,500.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Genetic Development (Incl. Sex Determination)

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

animal model | developmental genes | developmental/genetic disease | disease models, animal | embryo development | neural development | neural tube defects | spina bifida

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