Disruption of the mir137 Primary Transcript Results in Embryonic Lethality (2014)

Undergraduates: Rebecca Lee, Ann L. Collins, James J. Crowley, Randal J. Nonneman, Martilias S. Ferrel, Patrick F. Sullivan

Faculty Advisor: Patrick Sullivan
Department: Biology

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MicroRNA-137 (mir-137) is a brain-expressed regulator of gene expression that has been associated with schizophrenia. In order to determine mir137¿s role in brain development we characterized a mouse with a targeted disruption of mir137¿s host gene. We acquired a commercially available gene-targeted mouse for mir137 and characterized its effects on development, behavior and gene expression. Through a series of breeding experiments, we determined that targeting of this gene results in embryonic lethality in the homozygous state (P < 0.001). Matings from heterozygous x heterozygous mice resulted in a significantly increased number of resorbed embryos at embryonic day 11.5 (P<0.0001). Our attempt to rescue embryonic lethality by conditional knockout was unsuccessful¿likely due to the gene construct. The behavioral phenotype revealed no clear differences between wild type and heterozygous animals. Allele-specific gene expression data from heterozygous mice revealed little expression from the targeted allele but expression from the wild type allele. The overall levels of mir-137 micro RNA were not different between heterozygous and wild type animals. In conclusion, mice homozygous for the targeted allele must die after implantation but before embryonic day 11.5. Mice heterozygous for the targeted allele must upregulate expression of the remaining allele as indicated by gene expression and behavioral data. Therefore, the mir-137 host transcript is critical for proper development.