Gene Targeting into the 21st Century: Mouse Models of Human Disease from Cancer to Neuropsychiatric Disorders

This post describes an update seminar delivered by Dr. Mario R Capecchi at the 2017 HAPS Annual Conference in Salt Lake City.

Update seminar VI was a special one, given by Nobel laureate, Mario Capecchi. Having survived World War II in Italy, in part as a homeless orphan, Mario’s life story is a fascinating one.  He went on to become a graduate student at Harvard in the lab of the Nobel Prize winner and co-discoverer of the structure of DNA, James Watson.  In 2007, Mario Capecchi, now at the University of Utah, won the Nobel Prize in Physiology or Medicine jointly with Oliver Smithies and Martin Evans for their work on gene targeting. The ability to create knock-out mice is widely used to this day and has been a valuable means of mapping gene function.  Mario’s research talk at this year’s HAPS conference focussed on his current work which involves characterizing the different roles that the HOX gene family of transcription factors play during mouse development.  While most HOX (homeobox) gene members are involved in controlling embryonic body plan development in a cranio-caudal manner, Greer and Capecchi (2002) found that Hoxb8 plays a unique role in the mouse’s grooming behavior.

Most animals, including humans, perform some type of auto-grooming and in mice, a cephalocaudal pattern occurs, where the head is groomed first and the tail is groomed last.  Many regions of the brain including the brainstem appear to be involved.  Greer and Capecchi (2002) found that mice with a homozygous Hoxb8 complete loss-of-function knock-out, exhibited over-grooming to the point of hair loss and formation of deep lesions. The deep lesions suggest that the mice also may have reduced sensitivity to painful stimuli.  These mice spent twice as long grooming as wild type mice and also over-groomed their control littermates to the point of inducing hair loss.  Interestingly, in humans, obsessive-compulsive disorder (OCD) often manifests as excessive cleanliness and grooming (e.g. trichotillomania).  Greer and Capecchi mapped the murine expression of Hoxb8 and found that expression began at E7.5 in the primitive streak and yolk sac, spreading through the developing spinal ganglia, spinal cord, and then throughout grooming regions of the CNS in the adult mouse.  In many animals, the basal ganglia has been shown to be involved in modulating grooming behaviour (Aldridge et al., 1993; Berridge, 1989; Berridge and Fentress, 1987; Cromwell and Berridge, 1996; MacLean, 1985a, 1985b; Stein et al., 1992; Wise and Rapoport 1989;).  

In 2008, Capecchi’s lab (Chen et. al., 2008) found that the Hoxb8 gene was normally expressed in microglia cells, and that this expression appears to be required for regulating normal grooming time.  Chen et al. (2008) found that grooming dysfunction in Hoxb8 knockout mice, could be rescued with wild-type bone marrow transplantation. This makes sense as microglia descend from hemocytoblasts.  In addition, Chen et. al. also found that the Hoxb8 gene was normally expressed in the spinal cord where it seems to be responsible for appropriate responses to nociceptive and thermal stimuli.  In fact, Holstege et al. (2008) proposed that the nociceptive recipient interneurons in the dorsal spinal cord laminae I and II are deficient and disorganized in Hoxb8 knockout mice leading to reduced sensation.  Furthermore, Chen et. al. (2008), found that bone marrow transplantation did not rescue sensory defects, indicating that these 2 pathways of dysfunction were due to separate deficiencies (i.e. microglia cell and sensory neurons). Chen et al. (2008) found that deletion of Hoxb8 only in the hematopoietic cells resulted in mice with excessive grooming, but normal sensory responsiveness.

It is unclear how microglia cells are involved in grooming behaviour, however “immunological dysfunction is linked to many psychiatric disorders including OCD, major depression, bipolar disorder, autism, schizophrenia, and Alzheimer’s disease” Ashwood et al., 2006; da Rocha et al., 2008; Kronfol and Remick, 2000; Leonard and Myit, 2009; Strous and Shoenfeld, 2006 (Chen et al., 2008).   In this study, Hoxb8 mutant mice were found to have a deficiency of microglia (i.e. fewer microglia in the adult brain).  In terms of how microglia may control behaviour, it is speculated that microglia may be involved in modulating synaptic transmission as they surround synapses, perhaps playing a role in adjusting levels of neurotransmitters (e.g. serotonin).  In addition, microglia cells can secrete cytokines that affect both neuronal activity and longevity.  

At first glance it may seem strange that immune system cells, such as microglia, are involved in grooming.  However, upon further reflection, it does make sense that grooming behaviours may be controlled by the immune system, as the purpose of grooming in animals is to reduce the number of harmful pathogens.

Finally, it was noted that the Hoxb8 mutant mice did exhibit high levels of anxiety.   Anti-anxiety drugs were found to reduce the anxiety-induced grooming behaviour in Hoxb8 mutant mice and also improved their ability to perform the open maze test (which is a frequent measure of anxiety).   

As you can see, a lot of really interesting data was relayed to us in this update seminar and I’d really like to thank Mario Capecchi for such a thought-provoking talk!

Post from Dr. Zoë Soon, School of Health and Exercise Sciences, University of British Columbia Okanagan, BC, Canada

Aldridge, J.W., Berridge, K.C., Herman, M., and Zimmer, L. (1993). Neuronal coding of serial order: Syntax of grooming in the neostratum. Psychol. Sci. 4, 391-395.

Ashwood, P., Wills, S., and Vand Water, J. (2006). The immune response in autism: a new frontier for autism research. J. Leukoc. Biol. 80, 1-15.

Berridge, K.C. (1989). Substantia nigra 6-OHDA lesions mimic striatopallidal disruption of syntactic grooming chains: a neural systems analysis of sequence control. Psychobiol. 17, 377-385.

Berridge and Fentress (1987). Disruption of natural grooming chains after stritopallidal lesions. Psychobiol. 15, 336-342.

Chen, S.-K., Tvrdki, P., Peden, E., Cho, S., Wu, S., Spangrude, G., and Capecchi, M.R. (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141, 775-785.

Cromwell, H.C., and Berridge, K.C. (1996). Implementation of action sequences by a neostriatal site: a lesion mapping study of grooming syntax. J. Neurosci. 16, 3444-3458.

da Rocha, F.F., Correa, H., and Teixeira, S.L. (2008). Obsessive-compulsive disorder and immunology: a review. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1139-1146.

Greer, J.M. and Capecchi, M.R. (2002). Hoxb8 is required for normal grooming behavior in mice. Neuron 33, 23-34.

Holstege, J.C., de Graaf, W., Hossani,M., Cano, S.C., Jaarsma, D., van den Akker, E., and Deschamps, J. (2008). Loss of Hoxb8 alters spinal dorsal laminae and sensory responses in mice.  Proc. Natl. Acad. Sci. USA 105, 6338-6343.

Kronfol, Z., and Remick, D.G. (200). Cytokines and the brain: implications for clinical psychiatry. Am. J. Psychiatry 157, 683-694.

Leonard, B.E., and Myint, A. (2009). The psychoneuroimmunology of depression. Hum. Psychopharmacol. 24, 165-175.

MacLean, P.D. (1985a). Brain evolution relating to family, play, and the separation call. Arch. Gen. Psychiatry 42, 405-417.

MacLean, P.D. (1985b). Evolutionary psychiatry and the triune brain. Psychol. Med. 15, 219-221.

Stein, D.J., Shoulberg, N., Helton, K., and Hollander, E. (1992). The neuroethological approach to obsessive-compulsive disorder. Compr. Psychiatry 33, 274-281.

Strous, R.D., and Shoenfeld, Y. (2006). Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited.  J. Auoimmun. 27, 71-80.

Wise, S., and Rapoport, J. (1989). Obsessive-compulsive disorder: is it basal ganglia dysfunction? In Osbessive-Compulsive Disorders in Children and Adolsecents, J. Rapoport, Ed. (Washington, DC: American Psychiatric Press), pp 327-344.

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