Although neural substrates of mammalian female mating behavior have been described, the association between complex courtship activity and specific underlying mechanisms remains elusive. We have isolated a mouse line that unexpectedly shows altered female social behavior with increased investigation of males and increased genital biting. We investigated adult individuals by behavioral observation and genetic and molecular neuroanatomy methods. We report exacerbated inverse pursuits and incapacitating bites directed at the genitals of stud males. This extreme deviation from wild-type female courtship segregates with a deletion of the Hoxd1 to Hoxd9 genomic region. This dominant Atypical female courtship allele (HoxD(Afc)) induces ectopic Hoxd10 gene expression in several regions in newborn forebrain transitorily and stably in a sparse subpopulation of cells in the cornu ammonis fields of adult hippocampus, which may thus lead to an abnormal modulation in the sexual behavior of mutant females. The resulting compulsive sexual solicitation behavior displayed by the most affected individuals suggests new avenues to study the genetic and molecular bases of normal and pathological mammalian affect and raises the potential involvement of the hippocampus in the control of female courtship behavior. The potential relevance to human 2q.31.1 microdeletion syndrome is discussed.

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