Presenters: Nathan Beckett ; Emma Brenchley
Authors: Nathan Beckett, Emma Brenchley, Spencer Thacker, Wesley Allen, Dario Mizrachi, Michael Stark
Faculty Advisor: Dario Mizrachi
Institution: Brigham Young University
More than 300,000 infants worldwide are born each year with neural tube defects (NTD) (1). Tight junctions (TJ) are critical for the success of neural tube folding and prevention of NTDs. Claudins (CLDN) are essential components of the TJ and are key players in its function (2). In the chicken embryo, clostridium perfringens enterotoxin (CPE) induces NTDs, as it forms a complex with various CLDNs, causing cell death (3). Furthermore, NTDs have been connected more specifically to CLDN3, -4, and -8 (4). Our research focuses on creating a different strategy to selectively target CLDNs, thus identifying the specific contributions of each CLDN. In our study, we employ chimeric CLDN proteins developed by our laboratory. These are detergent independent proteins that produce molecules that retain the CLDN structure and their adhesive properties. We hypothesized that chimeric CLDNs would act in a specific manner rather than the promiscuous interactions fostered by CPE, revealing each CLDNs unique contributions to the formation of NTDs. Using chicken embryos, we have evaluated the role of chimeric CLDN3 and 8 when compared to CPE and the non-claudin chimeric base synthetic protein NMR836. We used NMR836 and PBS for controls. We present evidence that when compared to NMR836, chimeric CLDN3, -8, and CPE induced NTD in chicken embryos. We found that when compared to CPE that engendered NTDs at a rate of 26%, chimeric CLDN3 treatment resulted in a NTD rate of 23%, while CLDN8 produced NTDs at a rate of 35%. These results indicate that using chimeric CLDNs can help us identify specific mechanisms leading to NTD formation, and that these mechanisms may be controlled by single CLDNs and through mechanosensing networks. This new tool may be used in developmental research as an alternative for genetic manipulation with equal value.