title: MiR-302/367 regulate neural progenitor proliferation, differentiation timing, and survival in neurulation.
abstract: How neural progenitor cell (NPC) behaviors are temporally controlled in early developing embryos remains undefined. The in vivo functions of microRNAs (miRNAs) in early mammalian development remain largely unknown. Mir-302/367 is a miRNA cluster that encodes miR-367 and four miR-302 members (miR302a-d). We show that miR-302b is highly expressed in early neuroepithelium and its expression decline as development progresses. We generated a mir-302/367 knockout mouse model and found that deletion of mir-302/367 results in an early embryonic lethality and open neural tube defect (NTD). NPCs exhibit enhanced proliferation, precocious differentiation, and decreased cell survival in mutant embryos. Furthermore, we identified Fgf15, Cyclin D1, and D2 as direct targets of miR-302 in NPCs in vivo, and their expression is enhanced in mutant NPCs. Ectopic expression of Cyclin D1 and D2 increases NPC proliferation, while FGF19 (human ortholog of Fgf15) overexpression leads to an increase of NPC differentiation. Thus, these findings reveal essential roles of miR-302/367 in orchestrating gene expression and NPC behaviors in neurulation; they also point to miRNAs as critical genetic components associated with neural tube formation.
authors.affiliation: Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Si-Lu
authors.initials: SL
authors.lastname: Yang
authors.affiliation: Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Herrlinger
authors.affiliation: Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.affiliation: Biochemistry & Molecular Biology, University of Miami, Miami, FL 33136, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Lai
authors.affiliation: Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA. Electronic address: chen2014@uga.edu.
authors.forename: Jian-Fu
authors.initials: JF
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D020964:Embryo Loss / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009436:Neural Tube Defects / Q000235:genetics; D054261:Neurulation / Q000235:genetics*; D013997:Time Factors
chemical_list: D056742:Cyclin D2; C558265:MIRN302 microRNA, mouse; C000598715:MIRN367 microRNA, mouse; D035683:MicroRNAs; C108526:fibroblast growth factor 15, mouse; D019938:Cyclin D1; D005346:Fibroblast Growth Factors
keywords: Embryo development; MiR-302/367; Neural progenitors