Rescue of an Aggressive Female Sexual Courtship in Mice by CRISPR/cas9 Secondary Mutation in vivo

Abstract

We had previously reported [1] a mouse line carrying the Atypical female courtship (HoxDAfc) allele, where an ectopic accumulation of Hoxd10 transcripts was observed in a sparse population of cells in the adult isocortex, as a result of a partial deletion of the HoxD gene cluster (Figure 1A). Female mice carrying this allele displayed an exacerbated paracopulatory behavior, culminating in a severe mutilation of the studs’ external genitals. To unequivocally demonstrate that this intriguing phenotype was indeed caused by an illegitimate function of the HOXD10 protein, we use CRISPR/Cas9 technology to induced a microdeletion into the homeobox of the Hoxd10 gene in cis with the HoxDAfc allele [2]. Females carrying this novel HoxDDel(1-9)d10hd allele no longer mutilate males. We conclude that a brain malfunction leading to a severe pathological behavior can be caused by the mere binding to DNA of a transcription factor expressed ectopically. We also show that in HoxDAfc mice, Hoxd10 was expressed in cells containing Gad1 and Cck transcripts, corroborating our proposal that a small fraction of GABAergic neurons in adult hippocampus may participate to some aspects of female courtship.