miR-302 Is Required for Timing of Neural Differentiation, Neural Tube Closure, and Embryonic Viability
Ronald J. Parchem,
Nicole Moore,
Jennifer L. Fish,
Jacqueline G. Parchem,
Tarcio T. Braga,
Archana Shenoy,
Michael C. Oldham,
John L.R. Rubenstein,
Richard A. Schneider,
Robert Blelloch
Affiliations
Ronald J. Parchem
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Nicole Moore
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Jennifer L. Fish
Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Jacqueline G. Parchem
Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Tarcio T. Braga
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Archana Shenoy
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Michael C. Oldham
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
John L.R. Rubenstein
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA
Richard A. Schneider
Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
Robert Blelloch
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
The evolutionarily conserved miR-302 family of microRNAs is expressed during early mammalian embryonic development. Here, we report that deletion of miR-302a-d in mice results in a fully penetrant late embryonic lethal phenotype. Knockout embryos have an anterior neural tube closure defect associated with a thickened neuroepithelium. The neuroepithelium shows increased progenitor proliferation, decreased cell death, and precocious neuronal differentiation. mRNA profiling at multiple time points during neurulation uncovers a complex pattern of changing targets over time. Overexpression of one of these targets, Fgf15, in the neuroepithelium of the chick embryo induces precocious neuronal differentiation. Compound mutants between mir-302 and the related mir-290 locus have a synthetic lethal phenotype prior to neurulation. Our results show that mir-302 helps regulate neurulation by suppressing neural progenitor expansion and precocious differentiation. Furthermore, these results uncover redundant roles for mir-290 and mir-302 early in development.
