Gene-Environment Interactions Resulting in Neural Tube Defects with 22q11 Deletions

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Project Summary/Abstract Vitamin A and its biologically active metabolite Retinoic Acid (RA) play critical roles in patterning the developing embryo. Vitamin A deficiency or excess can cause a variety of developmental abnormalities, including defects in craniofacial and cardiac development and neural tube closure (Neural Tube Defects, NTDs). Thus, RA levels and signaling must be tightly regulated for normal development to occur. The embryo accomplishes this by altering the expression of the RA buffering machinery (RA synthetic and degradation enzymes along with RA binding proteins) to buffer small alterations in environmental exposure. Expression of many microRNAs (miRNAs) are regulated by RA signaling and miRNAs target the RA buffering machinery. Thus miRNAs are well positioned to mediate the negative and positive feedback loops that constitute the RA buffering capacity of the embryo. Our published data demonstrate that the LgDel mouse model of DiGeorge/22q11 deletion syndrome (22q11DS) exhibits dysfunctional RA buffering capacity. This results in increased incidence of NTDs when challenged with normally benign alterations in RA exposures. 22q11DS is the most frequent gene deletion syndrome in humans affecting 1 in 4000 live births. Features of 22q11DS vary widely and are most commonly associated with cardiac and craniofacial defects; however, many cases of NTDs are reported in patients with 22q11 deletions. Dgcr8/Pasha, is an essential component of the microprocessor complex responsible for generating mature miRNAs and is located within the 22q11 deletion. While Dgcr8+/- embryos do not exhibit obvious embryonic phenotypes, multiple defects in neuronal function are described in postnatal mice. Importantly, neurological deficits are accompanied by altered expression of miRNAs in the brain of Dgcr8+/- mice and other mouse models of 22q11DS as well as altered miRNA expression in peripheral blood and induced pluripotent stem cells (iPSCs) from 22q11DS patients. Thus haploinsufficiency of Dgcr8 can have a critical impact on expression of mature miRNAs, possibly creating a bottleneck in miRNA processing. The majority of NTDs, cardiac and craniofacial defects are due to complex gene-environment interactions. Some environmental triggers contributing to NTDs are known, yet few genetic factors have been identified. Moreover, HOW environmental and genetic factors interact to cause NTDs remains largely undetermined. Our finding that the LgDel embryo has dysfunctional RA buffering capacity developing NTDs provides a novel opportunity to dissect the mechanisms by which gene-environment interactions might tip the balance to cause NTDs. In this proposal we will test the hypothesis that haploinsufficiency of Dgcr8 in the LgDel embryo results in a bottleneck in miRNA processing and dysfunctional RA buffering capacity.