Experimental evidence has accumulated in the last two decades suggesting that periconceptional folic acid supplementation can reduce both the occurrence and the recurrence of craniofacial and neural tube defects in humans;however, the molecular mechanisms underlying these observations remain poorly understood. The failure to understand these mechanisms is critical, for although 50-70% of these defects can be prevented by periconceptional folic acid supplementation, there remains a significant number of babies born each year suffering with the consequences of these devastating malformations. Rothenberg and colleagues74 described the presence of autoantibodies for the folate receptor in sera from a high percentage of mothers of infants with neural tube defects. This speaks to the importance of this receptor in folate responsive birth defects. The objective of the proposed research program is to utilize a well characterized knockout mouse model for the folate receptor, as well as the creation of additional genetically modified mice, to test critical hypotheses involving the transcriptional regulation of folate responsive genes as they relate to neural tube and craniofacial development. With the aid of the genetically modified Folbp1 mouse models, the proposed experiments will examine the developmental processes that are compromised by the absence of sufficient available folate molecules. We will investigate the impact of folate transport defects on the development of the embryonic neural tube and craniofacies among the various Folbpl genotypes, and determine the role specific transcription factors have on regulating genes that are responsible for the specificity of the observed phenotypes. We propose to elucidate the impact a genetically determined folate deficiency has on epigenetic factors regulating embryonic gene expression. The identification and further elucidation of genes, their products, and their downstream signaling cascades critical for neural tube and craniofacial development will advance our understanding of the processes involved in both normal and abnormal development in these model systems, as well as in humans. Finally, we will explore the role of co-localized factors interacting with FOLBP1 and the role of this protein complex in neural and craniofacial morphogenesis. The hypothesis that the Folbp1 receptor functions in complexes with other proteins within the lipid raft of the cell membrane to act as a signaling molecule challenges existing preconceptions concerning the function of this protein.
| Cabrera, Robert M; Finnell, Richard H; Zhu, Huiping et al. (2012) Transcriptional analyses of two mouse models of spina bifida. Birth Defects Res A Clin Mol Teratol 94:782-9 |
| Boyles, A L; Ballard, J L; Gorman, E B et al. (2011) Association between inhibited binding of folic acid to folate receptor alpha in maternal serum and folate-related birth defects in Norway. Hum Reprod 26:2232-8 |
| Zhang, Zichao; Wlodarczyk, Bogdan J; Niederreither, Karen et al. (2011) Fuz regulates craniofacial development through tissue specific responses to signaling factors. PLoS One 6:e24608 |
| Iskandar, Bermans J; Rizk, Elias; Meier, Brenton et al. (2010) Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. J Clin Invest 120:1603-16 |
| Obican, Sarah G; Finnell, Richard H; Mills, James L et al. (2010) Folic acid in early pregnancy: a public health success story. FASEB J 24:4167-74 |
| Hill, Denise S; Wlodarczyk, Bogdan J; Palacios, Ana M et al. (2010) Teratogenic effects of antiepileptic drugs. Expert Rev Neurother 10:943-59 |
| Pisano, M Michele; Bhattacherjee, Vasker; Wong, Leeyean et al. (2010) Novel folate binding protein-1 interactions in embryonic orofacial tissue. Life Sci 86:275-80 |
| Bille, Camilla; Pedersen, Dorthe Almind; Andersen, Anne-Marie Nybo et al. (2010) Autoantibodies to folate receptor alpha during early pregnancy and risk of oral clefts in Denmark. Pediatr Res 67:274-9 |
| Salbaum, J Michael; Finnell, Richard H; Kappen, Claudia (2009) Regulation of folate receptor 1 gene expression in the visceral endoderm. Birth Defects Res A Clin Mol Teratol 85:303-13 |
| Zhu, H; Kartiko, S; Finnell, R H (2009) Importance of gene-environment interactions in the etiology of selected birth defects. Clin Genet 75:409-23 |
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