Learning, memory, behavior, and consciousness – perhaps the most amazing feats of evolution – emerge from the collective action of an extraordinarily diverse population of neurons. Although integral to the higher order properties of neural networks, the origins of neuronal diversity are incompletely understood.
Evolution tinkers: it tends to tweak existing systems rather than create from scratch. Therefore, it is reasonable to think that the origin of extraordinary cellular diversity in the nervous system may be discerned through comparison with other highly diverse cellular systems, like the immune system. In 1967, Dreyer, Grey and Hood recognized this, and remarked that common molecular mechanisms might underpin diversity in both systems. It has since become clear that functional diversity, plasticity, and systemic memory emanate from site-specific gene rearrangement during immunological development. Despite viable candidate loci in the nervous system (olfactory receptors and proto-cadherins), site-specific gene rearrangement has not been found in neural stem cells (NSCs) or neurons. Instead, genetic diversity in the nervous system – brought about by aneuploidy and retrotransposition – seems less specific; though probably no less significant.
Aneuploidy (the loss and/or gain of whole chromosomes) and retrotransposition (“jumping” by endogenous transposable elements) have both been observed in NSCs, and these changes persist in mature neurons. Diversity among neuronal genomes make the brain a genetic mosaic. Separately and together, different aneuploidies and de novo retrotransposition events create a multi-dimensional neuronal mosaic.
I hypothesize that genetic mosaicism can vary, even between identical twins, and contribute to individuality. Given a single somatic genome, some mosaics of this genome may lead to savants, while other mosaics may lead to sporadic neurological disease.
To test this hypothesis, I am developing single cell methods to measure the mosaic composition of individual brains. Employing these methods, I aim to understand how outliers arise in genomically homogenous populations.
Coming in February 2010 - Stem Cells and Cancer, a symposium at the Salk that I'm helping organize. Super speakers: Sean Morrison (HHMI, Michigan), Elaine Fuchs (HHMI, Rockefeller), Tannishtha Reya (Duke), and Hans Clevers (Hubrecht Institute)!!!
November 2009 - Lots of good neuronal MHCI stuff in Neuron, including reviews that cite my earlier paper in the Shatz lab, and publication of a collaboration from then with Akash Datwani and Stephen Smith's lab at Stanford.
McConnell, M.J., MacMillan, H.R., and J. Chun. (2009). Mathematical modeling supports substantial mouse neural progenitor cell death. Neural Development. 4: 28.
McConnell, M.J.*, Huang. Y.H.*, Datwani, A. and C.J. Shatz.. (2009). H2-Kb and H2-Db regulate cerebellar synaptic plasticity and motor learning. Proceedings of the National Academy of Sciences USA. 106(16) : 6784 - 6789
McConnell, M.J., Kaushal, D., Yang, A.H., Kingsbury, M.A., Rehen, S.K., Treuner, K., Helton, R., Annas, E., Chun, J., and C. Barlow. (2004). Failed clearance of aneuploid embryonic neural progenitor cells leads to excess aneuploidy in the Atm-deficient but not the Trp53-deficient adult cerebral cortex. The Journal of Neuroscience. 24(37): 8090 - 8096.
Zhao, X., Ueba, T., Christie, B., Barkho, B., McConnell, M.J., Nakashima, K., Lein, E.S., Eadie, B., Willhoite, A.R., Muotri, A.R., Summers, R.G., Chun, J., Lee, K.-F., and F.H. Gage. (2003). Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proceedings of the National Academy of Sciences USA. 100(11): 6777 - 6782.
Rehen, S.K.,* McConnell, M.J.,* Kaushal, D.,* Kingsbury, M.A., Yang, A.H., and J. Chun. (2001). Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proceedings of the National Academy of Sciences USA. 98(23): 13361 -13366.
* indicates equal contributions among authors
MJ McConnell, Ph.D
Salk Institute for Biological Studies
LOG-G
10010 N. Torrey Pines Rd.
La Jolla, CA 92037
mikemc at salk dot edu
Ph.D. |
UCSD, 2004 |
Post-doc |
Harvard Medical School, 2004 - 07 |