Mark F. Mehler

Alpern Professor of Neurology, Neuroscience and Psychiatry and Behavioral Sciences
University Chair, The Saul R. Korey Department of Neurology

Neural stem cell biology; pathogenesis of nervous system diseases; neural regeneration; developmental neuroscience.

Kennedy Center
Room 401

 

Laboratory of Molecular and Developmental Neuroscience (Program in Neural Stem Cell Biology and Regenerative Neurology)

The primary focus of our laboratory is on defining the regional localization and the biological properties of neural stem cells during embryonic and postnatal development and in the mature and the aging mammalian brain. We are also using stem cells as "biological probes" to elucidate the pathogenesis of a spectrum of complex and poorly understood acquired and genetic nervous system disorders. In these prototypical disorders, distinct profiles of regional stem cells or their more lineage-restricted neuronal or glial progeny undergo irreversible injury and death in response to acute or more chronic injury signals. Further, we are attempting to use the knowledge gained from these multidisciplinary studies to design innovative gene- and stem cell-based regenerative therapies. We are in the process of defining the dynamic roles of environmental factors, cell-cell signaling pathways and cell autonomous cues in promoting stem cell activation, expansion, lineage restriction, lineage commitment, cell cycle exit and terminal differentiation. We have identified specific transcription factor codes that endow the progeny of specific stem cell subpopulations with their unique cellular properties. These insights have already allowed us to "reprogram" different regional stem and progenitor cells both in vitro and in vivo to acquire the cellular properties of specific neuronal and glial subtypes that are lost in different classes of neurological diseases. We have also utilized embryonic stem cells, both to define initial stages of neural induction and patterning of the neural tube that have previously been difficult to examine experimentally, and as therapeutic reagents for those diseases of the nervous system in which multiple regional neuronal and glial subtypes are targeted. The ultimate aim of these studies is to identify innovative approaches to brain repair by activation of latent neural stem cell pools throughout the neuraxis to engage in selective regeneration of those cell types and neural network connections that have been compromised in specific disease states. The ability to activate and recruit these latent developmental programs to participate in selective neural regenerative responses will help to reestablish functional neural networks that preserve the integrity of previously acquired informational traces. More importantly, a better understanding of the pathogenesis of individual neurological disorders will allow us to more effectively employ our emerging neural regenerative strategies. For example, we are investing the possibility that early developmental abnormalities are important in the etiology of disorders of the aging brain, namely neurodegenerative diseases such as Alzheimer's, Huntington's and Parkinson's Diseases. We are also examining the hypothesis that primary brain tumors are caused by two distinct types of gene mutations: i. Mutations in selected genes that promote progressive stages of neuronal and glial maturation from neural stem cells, and ii. Mutations in different classes of genes that normally prevent mature glial cells from undergoing ectopic cell cycle reentry and dedifferentiation. Further, we are attempting to define the individual profiles of abortive endogenous stem and progenitor cell responses to those injury signals found in acute stroke and in demyelinating diseases such as multiple sclerosis. These studies will allow us to develop effective strategies to augment the endogenous stem cell response to injury by the use of novel therapeutic modalities that i. Selectively enhance positive response cues (regenerative cytokines and targeted transcription factors) and ii. Concurrently promote the removal of inhibitory signals (inactivation of inflammatory cytokines and blockade of receptors that mediate inhibition of neurite outgrowth and axonal pathfinding by myelin and associated breakdown products).

 

Selected Publications

Mehler, M.F., Rozental, R., Dougherty, M.J., Spray, D.C., Kessler, J.A. Cytokine Regulation of Neuronal Differentiation of Hippocampal Progenitor Cells. Nature 362:62-65 (1993).

Mehler, M.F., Kessler, J.A. Hematolymphopoietic and Inflammatory Cytokines in Neural Development. Trends in Neurosciences 20:357-365 (1997).

Mehler, M.F., Kessler, J.A. Bone Morphogenetic Proteins in the Nervous System. Trends in Neurosciences 20:309-317 (1997).

Marmur, R., Mabie, P.C., Gokhan, S., Song, Q., Kessler, J.A., Mehler, M.F. Isolation and Developmental Characterization of Cerebral Cortical Multipotent Progenitors. Developmental Biology 204:577-591 (1998).

Marmur, R., Kessler, J.A., Zu, G., Gokhan, S., Mehler, M.F. Differentiation of Oligodendroglial Progenitors from Cortical Multipotent Cells Requires Extrinsic Signals Including Activation of gp130/LIF beta-Receptors. Journal of Neuroscience 18:9800-9811 (1998).

Mehler, M.F., Gokhan, S. Postnatal Cerebral Cortical Multipotent Progenitors: Regulatory Mechanisms and Potential Role in the Development of Novel Neural Regenerative Strategies. Brain Pathology 9: 515-526 (1999).

Mehler, M.F. Mabie, P.C., Zhu, G., Gokhan, S., Kessler, J.A. Developmental Changes in Progenitor Cell Responsiveness to Bone Morphogenetic Proteins Differentially Modulate CNS Fate Decisions. Developmental Neuroscience 22: 74-85 (2000).

Mehler, M.F. Brain Dystrophin, Neurogenetics and Mental Retardation. Brain Research Reviews 32: 277-307 (2000).

Rozental, R., Srinivas, M., Gokhan, S., Urban, M., Dermietzel, R., Kessler, J.A., Spray, D.C., Mehler, M.F. Temporal Expression of Neuronal Connexins During Hippocampal Ontogeny. Brain Research Reviews 32:57-71 (2000).

Mehler, M.F., Gokhan, S. Mechanisms Underlying Neural Cell Death in Neurodegenerative Diseases: Alterations of a Developmentally-Mediated Cellular Rheostat. Trends in Neurosciences 23:605-611 (2000).

Mehler, M.F., Gokhan, S. Developmental Mechanisms in the Pathogenesis of Neurodegenerative Diseases. Progress in Neurobiology 63:337-363 (2001).

Gokhan, S., Mehler, M.F. Basic and Clinical Neuroscience Applications of Embryonic Stem Cells. The New Anatomist 265:142-156 (2001).

Mehler, M.F., Kessler, J.A. Cytokine Effects on CNS Cells: Implications for the Pathogenesis and Prevention of Stroke. In: Stroke and CNS Inflammation, Progress in Inflammation Research, Feuerstein, G. (ed.), Birkhauser-Verlag, pp.115-139 (2001).

Mehler, M.F. Mechanisms Regulating Lineage Diversity During Cerebral Cortical Neurogenesis and Gliogenesis. In: Cortical Development, Hohmann, C. (ed.), Results and Problems in Cell Differentiation, Vol. 39, Springer-Verlag, Heidelberg, pp. 27-52 (2002).

Mehler, M.F. Regional Forebrain Patterning and Neural Subtype Specification: Implications for Cerebral Cortical Functional Connectivity and the Pathogenesis of Neurodegenerative Diseases. In: Cortical Development, Hohmann, C. (ed.), Results and Problems in Cell Differentiation, Vol. 39, Springer-Verlag, Heidelberg, pp. 157-178 (2002).

Yung, S.-Y., Gokhan, S., Jurcsak, J., Molero, A., Abrajano, J.J., Mehler, M.F. Differential Modulation of BMP Signaling Promotes the Elaboration of Cerebral Cortical GABAergic Neurons or Oligodendrocytes from a Common Sonic Hedgehog-Responsive Ventral Forebrain Progenitor Species. Proceedings of the National Academy of Sciences, USA 99: 16273-16278 (2002).

Van De Water, T., Kojima, K., Tateya, I., Ito, J., Malgrange, B., Lefebvre, P.P., Staecker, H., Mehler, M.F. Stem Cell Biology of the Inner Ear and Potential Therapeutic Applications, In: Adult Stem Cells, Turksen, K. (ed.), Humana Press, New Jersey, pp. 269-288 (2004).