Highlights d Most mouse Cre driver lines tested exhibited variable rates of germline recombination d Germline recombination exhibits parental sex bias and target locus selectivity d Similar principles apply to multiple organisms and recombinase systems d Guidelines are provided for detecting and minimizing unwanted germline recombination

Graphical Abstract Highlights d The ubiquitin ligases Wwp1 and Wwp2 are essential for neuronal polarity acquisition d Wwp2 and Wwp2-intron-encoded miR-140 synergistically regulate neuronal development d miR-140 represses Fyn expression during neuronal development d Sox9 drives expression of Wwp1, Wwp2, and miR-140 in neurons SUMMARY The establishment of axon-dendrite polarity is fundamental for radial migration of neurons during cortex development of mammals. We demonstrate that the E3 ubiquitin ligases WW-Containing Proteins 1 and 2 (Wwp1 and Wwp2) are indispensable for proper polarization of developing neurons. We show that knockout of Wwp1 and Wwp2 results in defects in axon-dendrite polarity in pyramidal neurons, and their aberrant laminar cortical distribution. Knockout of miR-140, encoded in Wwp2 intron, engenders phenotypic changes analogous to those upon Wwp1 and Wwp2 deletion. Intriguingly, transcription of the Wwp1 and Wwp2/miR-140 loci in neurons is induced by the transcription factor Sox9. Finally, we provide evidence that miR-140 supervises the establishment of axon-dendrite polarity through repression of Fyn kinase mRNA. Our data delineate a novel regulatory pathway that involves Sox9-[Wwp1/Wwp2/miR-140]-Fyn required for axon specification, acquisition of pyramidal morphology, and proper laminar distribution of cortical neurons.