Hematopoietic origin of pathological grooming in Hoxb8 mutant mice
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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.
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Recent data from genome-wide association studies and analyses of postmortem human brain tissue have suggested that microglia and/or the complement cascade may also be involved in the development and pathogenesis of neurodevelopmental and psychiatric disorders.
“In addition to diseases associated with neurodegeneration, recent data from genome-wide association studies and analyses of postmortem human brain tissue have suggested that microglia and/or the complement cascade may also be involved in the development and pathogenesis of neurodevelopmental and psychiatric disorders (e.g., autism, obsessive compulsive disorder, schizophrenia, etc.) (Chen et al.,”
From Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner (2012) · cites this paper as Chen et al., 2010
The Introduction (page unavailable) reports that genome-wide association studies implicate immune-related genes in susceptibility to psychiatric disorders, and the Discussion links defective microglia to pathological grooming in mice. The paper does not report analyses of postmortem human brain tissue or implicate the complement cascade, so it supports only part of the attributed claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredKnockout of the developmentally expressed Hoxb8lox gene leads to perseverative grooming, which is reversed by bone marrow transplant from wild-type mice.
“knockout of the developmentally expressed Hoxb8lox gene leads to perseverative grooming, which is surprisingly reversed by bone marrow transplant from wild-type mice 89”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [89]
Mice lacking Hoxb8 in all cells or only in myeloid and endothelial cells spend twice as much time grooming as littermates, leading to hair loss and skin lesions reminiscent of trichotillomania.
“Mice lacking the homeobox gene Hoxb8 in all cells or only in myeloid and endothelial cells spend twice as much time grooming as do their littermates, leading to hair loss and skin lesions reminiscent of a human compulsive disorder known as trichotillomania (175).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [175]
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Csölle, C., Andó, R. D., Kittel, Á., Gölöncsér, F., Baranyi, M., Soproni, K., Zelena, D., Haller, J., Németh, T., Mócsai, A., et al. (2013) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711001933 · Cited by 108 · see citing works
“Recent studies have shown that certain behavioural patterns, such as pathological grooming, can be transferred from one animal to another by immune cell transplantation (Chen et al. 2010).”
BackgroundMicroglia ablation alleviates myelin-associated catatonic signs in mice
Janova, H., Arinrad, S., Balmuth, E., Mitjans, M., Hertel, J., Habes, M., Bittner, R. A., Pan, H., Goebbels, S., Begemann, M., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci97032 · Cited by 107 · see citing works
Microglia: dismantling and rebuilding circuits after acute neurological injury
Ziebell, J. M., Adelson, P. D., & Lifshitz, J. (2015) · Metabolic Brain Disease · doi:10.1007/s11011-014-9539-y · Cited by 84 · see citing works
The role of glial cells in synapse elimination
Chung, W.-S., & Barres, B. A. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2011.10.003 · Cited by 89 · see citing works
Inflammatory macrophage phenotype in BTBR T+tf/J mice
Onore, C. E., Careaga, M., Babineau, B. A., Schwartzer, J. J., Berman, R. F., & Ashwood, P. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00158 · Cited by 77 · see citing works
“Hoxb8 is a myeloid expressed gene associated with repetitive pathological grooming in mice deficient for the gene and excessive grooming is reduced with wild-type bone marrow transplant (Chen et al., 2010).”
BackgroundMice deficient in NRROS show abnormal microglial development and neurological disorders
Wong, K., Noubade, R., Manzanillo, P., Ota, N., Foreman, O., Hackney, J. A., Friedman, B. A., Pappu, R., Scearce-Levie, K., & Ouyang, W. (2017) · Nature Immunology · doi:10.1038/ni.3743 · Cited by 71 · see citing works
Microglia and Sensitive Periods in Brain Development
Dziabis, J. E., & Bilbo, S. D. (2021) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2021_242 · Cited by 42 · see citing works
Yang, X. W., & Lu, X.-H. (2011) · Current Opinion in Neurology · doi:10.1097/wco.0b013e32834451fb · Cited by 36 · see citing works
- Authors
- Chen, S.-K., Tvrdik, P., Peden, E., Cho, S., Wu, S., Spangrude, G., & Capecchi, M. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Utah (US)
- Corresponding author
- Capecchi, Mario R.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-05
- Volume
- 141
- Issue
- 5
- Pages
- 775-785
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2894573
- OpenAlex
- W2117434453
- Cited by
- 450
- References
- 42
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 23 · 2023: 20 · 2022: 16 · 2021: 27 · 2020: 19 · 2019: 24 · 2018: 24 · 2017: 37 · 2016: 27 · 2015: 32 · 2014: 42 · 2013: 51 · 2012: 46
- FWCI
- 48.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1173 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (R01GM021168)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD030701)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Hoxb8, trichotillomania, compulsive behavior, microglia, hematopoietic origin, bone marrow transplantation, nociception, neuropsychiatric disorders, immune dysfunction
- MeSH terms
- Animals, B-Lymphocytes, Behavior, Animal, Brain, Grooming, Humans, Obsessive-Compulsive Disorder, Spinal Cord, T-Lymphocytes, Bone Marrow Transplantation, Microglia, Homeodomain Proteins, Mice
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