David L. Paul

David L. Paul, PhD

Professor of Neurobiology, Harvard Medical School

We study the molecular structure and function of gap junctions, collec- tions of intercellular channels that allow the direct movement of small molecules between cells. These channels provide the electrical connections essential for the transmission of signals between many neurons as well as other excitable and non-excitable cells. Communication through gap junctions can also influence a diverse range of cellular behavior, including proliferation and differentiation. Over the last few years, we have cloned a family of genes, the connexins, that encode the components of intercellular channels. Recently we discovered that a hereditary dis-order, X-linked Charcot-Marie-Tooth (CMTX) disease, is associated with specific mutations in a connexin called Cx32. CMTX is an extremely common familial neuropathy characterized by slow, progressive motor and sensory loss. It mainly affects the peripheral nervous system, causing demyelination and slowing of nerve conduction velocities. We have shown that Schwann cells, which produce the myelin, make Cx32 and localize it to membranes near the nodes of Ranvier and at Schmitt-Lantermann incisures. Since myelinating Schwann cells do not establish gap junctions with one another and do not communicate, we have proposed that Cx32 forms intra-, not inter-, cellular junctions, providing an efficient radial pathway for diffusion of the signaling molecules between the Schwann cell body and peri-axonal cytoplasm. Thus, when Cx32 is nonfunctional, Schwann cells may not be able to support their peri-axonal cytoplasm and maintain normal myelination. However, some experimental observations don't completely fit this model. Using in vitro expression systems, we have tested the channel forming activity of Cx32 carrying certain CMTX mutations. Surprisingly, while most mutations result in nonfunctional channels, others appear to be completely normal. In addition, Cx32 knock-out animals do not develop CMT-like symptoms. Thus, basic questions about the etiology of CMTX and connexin function remain. To produce an animal model in which these issues can be addressed, we are using a knock-in strategy to replace normal Cx32 with a bona fide CMTX mutant. Cx32 may form "reflexive" gap junctions within a single Schwann cell. A highly diagrammatic cartoon illustrates how gap junction channels may connect paired membranes of adjacent gyres in compact myelin at an incisure of Schimdt-Lantermann. Cx32 is localized to incisures and paranodal membranes and is absent from compact myelin. Hypothetically, junctions could "short-circuit" the tube of cytoplasm connecting the Schwann cell body to its periaxonal cytoplasm, dramatically reducing the length of the path that nutrient or trophic molecules must traverse (dashed arrow). Although "reflexive" junctions have been noted in other cells, this is the first example with an obvious function.

"Over the last few years, we have cloned a family of genes, the connexins, that encode the components of intercellular channels."

Publications View
Expression of a dominant negative inhibitor of intercellular communication in the early Xenopus embryo causes delamination and extrusion of cells.
Authors: Authors: Paul DL, Yu K, Bruzzone R, Gimlich RL, Goodenough DA.
Development
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Intercellular channels in teleosts: functional characterization of two connexins from Atlantic croaker.
Authors: Authors: Bruzzone R, White TW, Yoshizaki G, Patiño R, Paul DL.
FEBS Lett
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Null mutations of connexin32 in patients with X-linked Charcot-Marie-Tooth disease.
Authors: Authors: Bruzzone R, White TW, Scherer SS, Fischbeck KH, Paul DL.
Neuron
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Differences in the expression of connexin genes in rat hepatomas in vivo and in vitro.
Authors: Authors: Neveu MJ, Sattler CA, Sattler GL, Hully JR, Hertzberg EL, Paul DL, Nicholson BJ, Pitot HC.
Mol Carcinog
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Voltage gating of connexins.
Authors: Authors: White TW, Bruzzone R, Goodenough DA, Paul DL.
Nature
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Gap junction systems in the rat vestibular labyrinth: immunohistochemical and ultrastructural analysis.
Authors: Authors: Kikuchi T, Adams JC, Paul DL, Kimura RS.
Acta Otolaryngol
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Enhancement of liver cell gap junction protein expression by glucocorticoids.
Authors: Authors: Ren P, de Feijter AW, Paul DL, Ruch RJ.
Carcinogenesis
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Colocalized alterations in connexin32 and cytochrome P450IIB1/2 by phenobarbital and related liver tumor promoters.
Authors: Authors: Neveu MJ, Babcock KL, Hertzberg EL, Paul DL, Nicholson BJ, Pitot HC.
Cancer Res
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Expression of gap junction proteins Cx26, Cx31.1, Cx37, and Cx43 in developing and mature rat epidermis.
Authors: Authors: Goliger JA, Paul DL.
Dev Dyn
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Selective interactions among the multiple connexin proteins expressed in the vertebrate lens: the second extracellular domain is a determinant of compatibility between connexins.
Authors: Authors: White TW, Bruzzone R, Wolfram S, Paul DL, Goodenough DA.
J Cell Biol
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