Hematopoietic origin of pathological grooming in Hoxb8 mutant mice

Mouse Hoxb8 mutants show unexpected behavior manifested by compulsive grooming and hair removal, similar to behavior in humans with the obsessive-compulsive disorder spectrum disorder trichotillomania. As Hox gene disruption often has pleiotropic effects, the root cause of this behavioral deficit was unclear. Here we report that, in the brain, Hoxb8 cell lineage exclusively labels bone marrow-derived microglia. Furthermore, transplantation of wild-type bone marrow into Hoxb8 mutant mice rescues their pathological phenotype. It has been suggested that the grooming dysfunction results from a nociceptive defect, also exhibited by Hoxb8 mutant mice. However, bone marrow transplant experiments and cell type-specific disruption of Hoxb8 reveal that these two phenotypes are separable, with the grooming phenotype derived from the hematopoietic lineage and the sensory defect derived from the spinal cord cells. Immunological dysfunctions have been associated with neuropsychiatric disorders, but the causative relationships are unclear. In this mouse, a distinct compulsive behavioral disorder is associated with mutant microglia.