Van Deren Donn A, Xu Ben, Nagarajan Naveen, Boulet Anne M, Zhang Shuhua, Capecchi Mario R
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
Department of Pathology & Laboratory Medicine, Abramson Family Cancer Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Mol Psychiatry. 2025 Sep 2. doi: 10.1038/s41380-025-03190-y.
Disruption of the Hoxb8 gene results in chronic anxiety and pathological overgrooming in mice. Using bilateral intracerebral cell transplantation, we demonstrate that mutant Hoxb8 microglia are causative for both behaviors. Mice contain two microglia lineages, Hoxb8 and non-Hoxb8 microglia. We proposed that the two lineages work as a binary system, in opposition to each other with Hoxb8 microglia functioning to reduce anxiety and grooming (function as brakes), whereas non-Hoxb8 microglia increase the levels of both behaviors (function as accelerators). This model makes a strong, unexpected prediction: mice containing only wild-type canonical non-Hoxb8 microglia should exhibit pathological levels of grooming and anxiety. We demonstrate that this is the case, providing strong support for both microglia functioning as a binary system and for the 'Accelerator/Brake' model. Since mice containing only non-Hoxb8 microglia represent mice with a loss of Hoxb8 function due to the absence of Hoxb8 microglia, the more intensive pathology associated with Hoxb8 mutant mice must reflect that mutant mice have both gain and loss of function components. We identify and quantify the relative contribution of each component.
Hoxb8基因的破坏会导致小鼠出现慢性焦虑和病理性过度梳理行为。通过双侧脑内细胞移植，我们证明突变的Hoxb8小胶质细胞是这两种行为的病因。小鼠含有两种小胶质细胞谱系，即Hoxb8小胶质细胞和非Hoxb8小胶质细胞。我们提出，这两种谱系作为一个二元系统发挥作用，彼此对立，其中Hoxb8小胶质细胞起到减轻焦虑和梳理行为的作用（起到刹车作用），而非Hoxb8小胶质细胞则会增加这两种行为的水平（起到加速器作用）。该模型做出了一个强有力的、出人意料的预测：仅含有野生型典型非Hoxb8小胶质细胞的小鼠应该表现出病理性的梳理和焦虑水平。我们证明情况确实如此，这为小胶质细胞作为二元系统发挥作用以及“加速器/刹车”模型提供了有力支持。由于仅含有非Hoxb8小胶质细胞的小鼠代表因缺乏Hoxb8小胶质细胞而失去Hoxb8功能的小鼠，与Hoxb8突变小鼠相关的更严重病理学现象必然反映出突变小鼠同时具有功能获得和功能丧失成分。我们识别并量化了每个成分的相对贡献。
