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David Paul, Ph.D

Professor of Neurobiology

Harvard Medical School
Dept of Neurobiology
220 Longwood Ave
Boston, MA 02115
Telephone: 617-432-1203
Fax: 617-734-7557
Email: dpaul@hms.harvard.edu
Predocs: 1 Postdocs: 3 Completed PhD's: 2

David Paul

We are exploring the function of gap junctions in the nervous system.  Gap junctions are collections of intercellular channels allowing direct movement of small molecules between cells.  Such channels provide a mechanism for propagation of excitation among neurons, where they constitute electrical synapses, and also provide a route of signal transduction essential for glial cell functioning in both central and peripheral nervous systems.  However, since there are no pharmacologic inhibitors of intercellular channels, precisely defining the roles of intercellular communication is a major challenge.  To that end, we have produced a series of alterations in the >20 related genes encoding connexins (Cx), the intercellular channel forming proteins.

One line of study in our lab involves myelination.  We have shown that a common peripheral demyelinating neuropathy, X-linked Charcot-Marie-Tooth disease, is caused by mutations in Cx32, which is expressed in myelinating Schwann cells.  Schwann cells do not make gap junctions with neighboring cells but establish ‘reflexive” junctions between the wraps of myelin at the paranode and incisures.  Although clearly important, the functions of such gap junctions, connecting different parts of the same cell, are not at all clear.  Schwann cells also express Cx29, which is concentrated at juxtaparanodal membranes and displays very little overlap in distribution with Cx32.  Knockouts of Cx29 display progressive hearing loss, due to demyelinating at the soma of spiral ganglion neurons.  Curiously, Cx29 is not organized into gap junction-like structure.  Like Cx32, its physiological importance is clear but its specific functions are not.  Connexin expression is also important for central myelination.  Oligodendrocytes, unlike Schwann cells, establish junctional contacts with other cells, not with each other but with astrocytes.  Oligodendrocytes and astrocytes each express a different set of three connexins and it is not clear what the contributions of each are.  However, double knockouts of oligodendrocyte Cx32 and Cx47 display central demyelination and extensive neuronal loss during early postnatal development.  We are currently exploring the nature of coupling between central glia and the functions of each connexin.

Another major research project focuses on the retina, where gap junctions are found between many neuronal cells. and participate in retinal circuitry in critical ways.  We have shown that loss of Cx36, expressed by AII amacrine cells and photoreceptors, eliminates all rod-driven ON signaling to ganglion cells.  Because anatomical and psychophysical studies suggest the existence of several rod signaling pathways, our data indicate that they all involve signaling through electrical synapses containing Cx36.  To explore this, we are employing cell-specific knockouts to genetically dissect rod signaling pathways and other retinal circuitry.

 

References:

  • Deans, MR, Volgyi B, Goodenough DA, Bloomfield SA and PAUL DL.  2002.  Cx36 is essential for transmission of rod-mediated visual signals in the mammalian retina.  Neuron 36: 703-712

  • Menichella DM, Goodenough DA, Sirkowski E, Scherer SS, PAUL DL.  2003.  Connexins are Critical for Normal Myelination in the Central Nervous System.  J. Neuosci. 23: 5963-5973

    Altevogt BM and PAUL DL.  2004.  Four classes of intercellular channels between glial cells in the CNS.    J. Neurosci. 24: 4313-23

  • Tang W, Zhang Y, Ahmad S, Chang Q, Dahlke I, Yi H, Chen P, PAUL DL, Lin X.  2005.   Connexin29 is highly expressed in cochlear Schwann cells and it is required for the normal development and functions the cochlea of mice.  J. Neurosci. 26: 1991-9.

  • Menichella DM, Majdan M, Awatramani R, Goodenough DA, Sirkowski E, Scherer SS, PAUL, DL.  2006.  Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity..  J. Neurosci. 26:10984-991.