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).

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS096176-04
Application #
9418121
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Morris, Jill A
Project Start
2016-04-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
Shao, Qiang; Herrlinger, Stephanie; Zhu, Ya-Nan et al. (2017) The African Zika virus MR-766 is more virulent and causes more severe brain damage than current Asian lineage and dengue virus. Development 144:4114-4124
Shao, Qiang; Herrlinger, Stephanie; Yang, Si-Lu et al. (2016) Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage. Development 143:4127-4136
Yang, Mei; Liang, Chen; Swaminathan, Kunchithapadam et al. (2016) A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Sci Adv 2:e1601167
Yang, Si-Lu; Yang, Mei; Herrlinger, Stephanie et al. (2015) MiR-302/367 regulate neural progenitor proliferation, differentiation timing, and survival in neurulation. Dev Biol 408:140-50
Yang, Mei; Yang, Si-Lu; Herrlinger, Stephanie et al. (2015) Lin28 promotes the proliferative capacity of neural progenitor cells in brain development. Development 142:1616-27