874: Overexpression of YAP rescue maternal diabetes induced neural tube defects

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Maternal Diabetes is associated with higher risk of neural tube defects. The Hippo/YAP pathway play central role in cranial neural crest development. In present study, we aim to determine whether YAP is inactivated (phosphorylated at Ser127) in maternal diabetes induced neural tube defects and whether Hippo/YAP pathway plays a causal role in maternal diabetes induced neural tube defects. A transgenic mouse carry YAP wild-type under nestin promoter as well as Yap constitutive active form (Ser127Ala) was generated to study how these transgenic mice response to maternal diabetes induced neural tube defects. Neural epithelium conditional knockout (cKO) of the Hippo pathway effectors, YAP/TAZ, were also generated by crossing the YAP/TAZ floxed mice to mice with Cre driven under the nestin promoter. Neural tube defects were evaluated at the embryo day 9.5 or 10.5. We found that YAP is inactivated in maternal diabetes induced neural tube defects compare to normal littermates, while the constitutive active YAP transgenic mice also induce neural tube defects (51.3% vs Yap wild type) under normal condition. In the meantime, neural epithelium specific deletion of either YAP or YAP/TAZ results in 100% neural tube defects under normal condition. However, neural specific overexpression of YAP wild type significantly blocks maternal diabetes induced neural tube defects (from 35.0% for non transgenic mice to 12.1% for transgenic mice). Our further experiments suggest that this achieved probably through the restoring of the planar cell polarity pathway. Our findings indicate that the YAP is crucial for neural tube development and its activity is under fine-tune by different signaling pathways.