Brian Howell, PhD
- Assistant Professor of Neuroscience and Physiology
- Assistant Professor of Neuroscience Graduate Program
Research Programs and Affiliations
- Biomedical Sciences Program
- Neuroscience Program
- Neuroscience and Physiology
- Physiology Program
- Research Pillars
Education & Fellowships
- PhD: McGill University, Montreal, Quebec, 1992
- BS: University of Western Ontario, Canada, 1985
- NIH, Bethesda MD, 1999–2008
- The signal transduction events that regulate the functional organization of neurons in the brain, and the phenotypes caused by defects in the genes that encode these signaling molecules.
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Brain development is an exquisitely regulated phenomenon, whereby waves of differentiation produce diverse classes of neurons, oligodendrocytes and finally, astrocytes. Ultimately these cells, particularly the neurons, organize into functional networks that receive, integrate and transmit information. My lab studies how molecular signaling regulates the migration of neurons from their site of origin to destinations where they extend processes, form synapses and integrate into networks. One of our focuses is to investigate how the Reelin signaling pathway influences the positioning of distinct neuronal classes into stereotypical layers in the brain. Reelin, a secreted ligand, induces the tyrosine phosphorylation of the intracellular docking protein Dab1 by clustering the neuronal receptors ApoER2 and VLDLR and activating Src-family kinases. The tyrosine phosphorylation of Dab1 generates signaling complexes that includes the molecules Nckbeta, Crk, CrkL and PI3K. These complexes regulate the behavior of neurons as they migrate, enabling them to settle into layers. We have recently shown that Reelin signaling influences the extension of the Golgi apparatus into neuronal dendrites and the ability of neurons to polarize. We are currently investigating how these cellular behaviors influence neuronal positioning and other neuronal properties regulated by Reelin signaling.
My lab is also focused on genetic modifiers of the Reelin signaling pathway that participate in Tau phosphorylation. Tau is hyperphosphorylated in Alzheimer's and other neurological diseases and leads to the formation of neurofibrillary tangles, ultimately leading to synaptic dysfunction and neuronal death. In Reelin pathway mutants, Tau is phosphorylated in a mouse strain-dependent manner. We took advantage of this phenotype to identify Stk25 as a modifier of Reelin signaling. We found that in addition to influencing Tau phosphorylation, Stk25 regulates Golgi morphology and neuronal polarization. It interacts with the Golgi matrix protein GM130 and the LKB1-STRAD pathway. Stk25 links the LKB1-STRAD pathway, which is known to regulate cell polarization, to changes in Golgi apparatus morphology and positioning during neuronal development. We are currently investigating how Stk25 converges with the Reelin-Dab1 signaling pathway to regulate brain development. These studies have promise for understanding developmental as well as neurodegenerative diseases.
1. Howell, B.W., Hawkes, R., Soriano, P., and Cooper, J.A. (1997). Neuronal position in the developing brain is regulated by mouse disabled. Nature, 389: 733-737.
2. Verbeek, D.S., Knight, M.A., Harmison G.G., Fischbeck K.H., and Howell, B.W. (2005) Protein kinase C gamma mutations in spinocerebellar ataxia 14 increase kinase activity and alter membrane targeting. Brain 128:436-442.
3. Pramatarova, A., Ochalski, P.G., Lee, C-H., Howell, B.W. (2006) Mouse Disabled 1 regulates the nuclear position of neurons in a Drosophila eye model. Mol. Cell. Biol. 26:1510-1517.
4. Andrade, N., Komnenovic, V., Blake, S., Jossin, J., Howell, B., Goffinet, A., Schneider, W.J., Nimpf, J. (2007) ApoER2/ VLDL receptor and Dab1 in the rostral migratory stream function in postnatal neuronal migration independently of Reelin. Proc. Natl. Acad. Sci. 104:8508-8513.
5. Pramatarova, A., Chen, K.-L., Howell, B.W. (2008) A genetic interaction between the APP and Dab1 genes influences brain development. Mol. Cell. Neurosci.37:178-186.
6. Matsuki, T., Pramatarova, A., Howell B.W. (2008) Reduction of Crk and CrkL expression blocks Reelin-induced dendritogenesis. J. Cell Sci. 121:1869-1875.
7. Hoe, H. S., Lee, K. J. , Carney, R. S., Lee, J., Markova, A., Lee, J. Y., Howell, B. W., Hyman, B. T., Pak, D. T., Bu, G., and Rebeck, G. W. (2009) Interaction of reelin with amyloid precursor protein promotes neurite outgrowth. J. Neurosci. 29:7459-73.
8. Matsuki, T., Matthews, R.T., Cooper, J.A., van der Brug, M.P., Cookson, M.R., Hardy, J.A., Olson, E.C., Howell, B.W. (2010) Reelin and Stk25 have opposing roles in neuronal polarization and dendritic golgi deployment. Cell 143:826-836.
9. Matsuki, T., Zaka, M., Guerreiro, R., van der Brug, M.P., Cooper, J.A., Cookson, M.R., Hardy, J.A., Howell, B.W. (2012) Identification of stk25 as a genetic modifier of Tau phosphorylation in dab1-mutant mice. PLoS ONE 7(2): e31152.
10. Teixeira, C.M., Kron, M.M., Masachs, N., Zhang, H., Lagace, D.C.Martinez, A., Reillo, I., Duan, X., Bosch, C., Pujadas, L., Brunso, L., Song, H., Eisch, A.J., Borrell, V., Howell, B.W., Parent, J.M., Soriano, E. (2012) Cell-autonomous inactivation of the Reelin pathway impairs adult neurogenesis in the hippocampus. J. Neurosci. 32:12051-12065.
11. Brunne, B., Franco, S., Bouché, E., Herz, J., Howell, B., Müller, U., May, P., Frotscher, M., Bock, H.H. (2013) Role of the postnatal radial glial scaffold for the development of the dentate gyrus as revealed by Reelin signaling mutant mice. Glia (in press)