The overall goal of this proposal is to establish a novel mechanism whereby microRNA (miRNA) miR-302/367 regulates neural tube closure (NTC). Disruption of NTC leads to neural tube defect (NTD), which is the second most common birth defect in humans affecting 1 to 1,000 births. However, the regulators and mechanisms that control NTC at post-transcriptional gene regulation levels remain largely unknown. We have created the first miRNA mouse model of NTD. We found that depletion of miR-302/367 leads to NTD and embryonic lethality. Neural precursor cells (NPCs) exhibit reduced proliferation, premature differentiation, and decreased survival in the mutant embryos. Importantly, we have identified individual miRNA targets with potent roles in specific cellular behaviors that are affected in mutant embryos. In addition, we found that miR-302/367 is associated with an RNA binding protein Lin41 to regulate gene expression; depletion of Lin41 also leads to NTD. These preliminary data lead to a novel hypothesis that miR-302/367 interacts with Lin41 to coordinately control multiple neural precursor cell (NPC) behaviors by regulating different miRNA targets during neural tube closure (NTC). In this project, we will determine miR-302/367 functions and their action mechanisms during neural tube closure.
Three specific aims will be pursued: 1) Determine the developmental and cellular basis of neural tube defect (NTD) in miR-302/367 mutant mice; 2) Test whether individual genes that we have identified as targets of miR-302 mediate specific cellular behaviors during neural tube closure; 3) Test the hypothesis that miR-302 functions together with Lin41 to regulate gene expression and NPC behaviors during neural tube closure. Together, these studies will improve our understanding of genetic factors associated with NTD and provide novel insights into mechanisms underlying neural tube closure and neural tube defect (NTD).
Neural tube closure (NTC) is the process whereby a flat sheet of neural plate is folded into a neural tube. Disruption of NTC leads to neural tube defects (NTD), the second most common birth defect in humans, affecting 1 in 1,000 births. Preventing NTD requires the understanding the mechanism of NTC and the biological basis of NTD. This project seeks to establish a novel mechanism by which microRNA (miRNA) regulates NTC and understand how its disruption leads to NTD.
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