It is becoming increasingly common for scientists to uncover new functions for molecules they thought they understood. A case in point is the discovery that key regulators of immunity, major histocompatibility class I (MHC class I) molecules, play an unexpected role in neurodevelopment. Dr. Daniel Kaufman and his research team from the University of California, Los Angeles, have demonstrated that over-expression of MHC class I molecules affects hippocampal morphology and function (Wu et al. 2010).
MHC class I molecules consist of three main components: a heavy chain with a peptide binding groove, B2 microglobulin (B2M) and a degraded protein fragment. Conventionally, these molecules are associated with immune function. They integrate themselves into a cell's surface and display their degraded protein fragments extracellularly – making them easily detectable by immune system cells. If the degraded protein fragments are foreign antigens (e.g., from a bacteria or virus), the immune system mounts an attack against them when they are encountered elsewhere in the body.
MHC class I molecules were once thought to play a minor role in the nervous system. However, recent studies have shown that they are widely expressed by neurons, and their deficiency causes a variety of neurological problems. Mice deficient in these molecules have abnormal neural circuitry in the hippocampus, altered motor learning and defects in the dorsal lateral geniculate nucleus (dLNG) – the part of the brain that processes information from the retina. Additionally, paired immunoglobulin-like receptor B (PirB), an MHC class I molecule receptor classically associated with the innate immune system, has been shown to play a role in the synaptic plasticity of the visual cortex.
Because previous studies had focused on the effects of MHC class I molecule deficiency on neurodevelopment, Dr. Kaufman's team focused its research on the neurodevelopmental effects of MHC class I molecule over-expression. From the Scripps Institute, the researchers obtained a mouse harboring a transgene consisting of a neuron-specific enolase promoter linked to a Db heavy chain cDNA (matching the endogenous H-2D MHC class I molecule allele of the mouse). They introgressed the transgene from this "NSE-Db" mouse into the C57BL/6J (B6J, 000664) background, producing a B6J NSE-Db mouse.
Dr Kaufman's team confirmed that the dLGN morphology of B2m-deficient B6.129P2-B2mtm1Unc/J (002087) mice is abnormal and determined that it is also abnormal in B6J NSE-Db mice. Additionally, they found that some hippocampal regions of B6J NSE-Db mice have deficient neural circuitry characterized by poor synaptic connections and an abnormally low number of principal neurons. B6J NSE-Db mice also have defective neuro-repair responses.
In summary, the Kaufman team demonstrated a role for MHC class I molecules in normal brain function by showing that their over-expression impairs neurodevelopment in mice. Future studies of the role of these molecules in the nervous system may improve therapies for nervous system disorders in humans.
Wu Z-P, Washburn L, Bilousova TV, Boudzinskaia M, Escande-Beillard N, Querubin J, Dang H, Xie C-W, Tian J, Kaufman DL. 2010. Enhanced neuronal expression of major histocompatibility complex class I leads to aberrations in neurodevelopment and neurorepair, J Neuroimmunol [Epub ahead of print].