School of Medicine

Date

11th March 2010

In recent years, the TNFR superfamily member death receptor 3 (DR3, TNFRSF25, Apo3, LARD, TRAMP, TR3) and its ligand TL1A have emerged as important regulators of inflammation and autoimmunity, with both DR3^ko and TL1A^ko mice showing resistance to multiple models of disease including inflammatory arthritis, experimental autoimmune encephalomyelitis and allergic lung inflammation. This has been supported by proof-of-principle studies that showed anti-TL1A therapies could ameliorate these or related disease models, which has underscored the therapeutic potential of anti-TL1A in inflammatory diseases. However, the function of the DR3/TL1A pathway in the absence of immune activation has remained a mystery.

This week, Eddie Wang and his laboratory in collaboration with colleagues in Cardiff University BIOSI (Alun Davies, Stephen Dunnett), Cambridge (Aviva Tolkovsky) and Barcelona (Jordi Alberch) have published in the Journal of Neuroscience on another essential role for DR3, this time on neurological function. DR3^ko mice spontaneously develop multiple behavioural defects with age including dyskinesia and hyperactivity that is associated with increased striatal dopamine and impaired innervation between the cortex and the striatum. This suggests DR3 signalling is vital for maintenance of healthy neuronal networks, the break up of which leads to disruption of motor control.

This work uncovers an important piece of the jigsaw to DR3 biology, providing some explanation to why DR3 is maintained in the genome. Why a gene that seems essential for brain function should also be involved in the control of peripheral inflammation is still a mystery. There are also some fundamental differences between mouse and man that require consideration when interpreting DR3’s function in humans. These include more complex genetics (humans have a DR3 gene duplication not found in mouse) and biochemistry (humans express Decoy Receptor 3, another ligand for TL1A, not found in mouse). Further research into these areas is required before a full appreciation of the therapeutic potential of this TNFR superfamily member can be achieved.

DR3 expression is restricted to neurons

Full Reference

Twohig, J.P., Roberts, M., Gavalda, N., Rees-Taylor, E., Giralt, A., Adams, D., Bull, M.J., Calder, C.J., Cuff, S., Yong, A.A., Alberch, J., Davies, A., Dunnett, S., Tolkovsky, A., & Wang, E.C.Y. (2010) Age-dependent maintenance of motor control and corticostriatal innervation by death receptor 3. Journal of Neuroscience, 30: 3782-3792 (10.1523/JNEUROSCI.1928-09.2010).

Journal Highlight

This Week in the Journal. Development/Plasticity/Repair. Death receptors help maintain corticostriatal connections. Journal of Neuroscience, 30(10): i-i.