Exencephaly is a form of neural tube defect that results from the failure of the anterior neural tube to close followed by the outward expansion of the neural tissue. It is estimated that neural tube defects occur in 1 in 1,000 births in humans, and both environmental and genetic factors contribute to these complex disorders. DEAF-1 is a transcriptional regulator that is required for embryonic development. The investigators have produced Deaf-1 knockout mice and observed that 100% of the Deaf-1-/- mice die at or shortly after birth, and 68% of the mice display exencephaly. Adult mice heterozygous for a Deaf-1 null allele () display anxiety behavior, suggesting DEAF-1 deficiencies may alter brain function. DEAF-1 promotes apoptosis, potentially through interactions with other factors such as LMO4, p53, HSP90, and DNA-protein kinase. The investigators hypothesize that DEAF-1 protein is essential for neural tube closure through the transcriptional regulation of target genes and by interactions with protein partners controlling cell proliferation and apoptosis. To test this hypothesis, they propose, in Specific Aim 1, to evaluate cellular proliferation, apoptosis, and potential alteration of DEAF-1 protein interactions or signaling partners during neural tube closure in the mouse embryo;
in Specific Aim 2, to examine the effects of genotoxic stress on p53 expression in mouse embryo fibroblasts (MEFs) isolated from Deaf-1 knockout embryos. The investigators have found that DEAF-1 is increased and/or stabilized in human cancer cell lines exposed to genotoxic agents, that there are protein-protein interactions between DEAF-1 and p53, and that DEAF-1 can increase transcription of a p53 promoter, and they will examine these interactions in MEFs. The results of this study may give insight into how dysregulation and mutations in DEAF-1 may contribute to neural tube defects and tumor formation in humans.
The research environment and objectives of this proposal are consistent with the goals of the NIH Academic Research Enhancement Award (AREA) R15. The proposed research will be conducted by investigators (J. Huggenvik and M. Collard) and students (both undergraduate and graduate students) at Southern Illinois University School of Medicine in Carbondale, Illinois. The research is based on the observation that Deaf-1 null allele (-/-) mice show exencephaly and die shortly before or after birth, while Deaf-1 null allele (+/-) mice appear outwardly normal and survive to adulthood but display behavioral differences. The proposed studies will provide greater insight into possible mechanisms of neural tube defects and behavioral problems in humans.
| Jensik, Philip J; Vargas, Jesse D; Reardon, Sara N et al. (2014) DEAF1 binds unmethylated and variably spaced CpG dinucleotide motifs. PLoS One 9:e115908 |
| Vulto-van Silfhout, Anneke T; Rajamanickam, Shivakumar; Jensik, Philip J et al. (2014) Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems. Am J Hum Genet 94:649-61 |
| Jensik, Philip J; Huggenvik, Jodi I; Collard, Michael W (2012) Deformed epidermal autoregulatory factor-1 (DEAF1) interacts with the Ku70 subunit of the DNA-dependent protein kinase complex. PLoS One 7:e33404 |
