Summary Mouse Hoxb8 mutants show unexpected behavior manifested by compulsive grooming and hair removal similar to humans with OCD-spectrum disorder trichotillomania. Since 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. Further, this pathological behavior is rescued by transplantation with wild-type bone marrow. It has been suggested that the grooming dysfunction results from a nociceptive defect, also exhibited by Hoxb8 mutant mice. However, bone marrow transplantation does not rescue the sensory defect. Also, disruption of Hoxb8 in the hematopoietic lineage recapitulates pathological grooming, without conferring nociceptive insensitivity. Conversely, disruption of Hoxb8 in the spinal cord, results in generating the sensory defects, without induction of pathological grooming. 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.

Olig gene expression is proposed to mark the common progenitors of motoneurons and oligodendrocytes. In an attempt to further dissect the in vivo lineage relationships between motoneurons and oligodendrocytes, we used a conditional cell-ablation approach to kill Olig-expressing cells. Although differentiated motoneurons and oligodendrocytes were eliminated, our ablation study revealed a continuous generation and subsequent death of their precursors. Most remarkably, a normal number of oligodendrocyte precursors are formed at day 12 of mouse development, after all motoneuron precursors have been killed. The data presented herein supports a sequential model in which motoneuron and oligodendrocyte precursors are sequentially generated in vivo from neuroepithelial stem cells, but do not share a common lineage-restricted progenitor.

Background: Sepp1 transports selenium, but its complete role in selenium homeostasis is not known. Results: Deletion of Sepp1 in hepatocytes increases liver selenium at the expense of other tissues and decreases whole-body selenium by increasing excretion. Conclusion: Sepp1 production by hepatocytes retains selenium in the organism and distributes it from the liver to peripheral tissues. Significance: Sepp1 is central to selenium homeostasis.

Here we describe a practical Cre-loxP and piggyBac transposon-based mutagenesis strategy to systematically mutate coding sequences and/or the vast noncoding regions of the mouse genome for large-scale functional genomic analysis. To illustrate this approach, we first created loxP-containing loss-of-function alleles in the protocadherin alpha, beta and gamma gene clusters (Pcdha, Pcdhb and Pcdhg). Using these alleles, we show that, under proper guidance, Cre-loxP site-specific recombination can mediate efficient trans-allelic recombination in vivo, facilitating the generation of large germline deletions and duplications including deletions of Pcdha, and Pcdha to Pcdhb, simply by breeding (that is, at frequencies of 5.5%-21.6%). The same breeding method can also generate designed germline translocations between nonhomologous chromosomes at unexpected frequencies of greater than 1%. By incorporating a piggyBac transposon to insert and to distribute loxP sites randomly throughout the mouse genome, we present a simple but comprehensive method for generating genome-wide deletions and duplications, in addition to insertional loss-of-function and conditional rescue alleles, again simply by breeding.