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My chief scientific interest is the pathogenesis of peripheral neuropathies. This began in my Ph.D. thesis, when I was used anatomical techniques (electron microscopy and retrograde tracing with HRP) to study how axons regenerate in the peripheral nerves of goldfish (Scherer and Easter, 1984; Scherer, 1986). These studies demonstrated that axonal regeneration in fish, which had been considered to have special regenerative abilities (Sperry and Arora, 1965), was actually similar to that in mammals. I was hooked, so after graduation, I chose to train in the Department of Neurology at Penn, which had a distinguished faculty (Arthur Asbury, Mark Brown, David Pleasure, John Sladky, Austin Sumner) who were doing important investigations on the clinical and basic scientific aspects of neuropathy. Following my residency I did a neuromuscular fellowship, combining clinical work in neuromuscular diseases with basic scientific work in the lab of Dr. John Kamholz, who was interested in the molecular biology of myelination. During my fellowship, I became increasingly interested in the pathogenesis of inherited neuropathies, especially demyelinating neuropathies. In a career-altering collaboration with Dr. Kurt Fischbeck (Bergoffen et al., 1993), then a colleague at Penn, I was involved in the discovery that mutations in GJB1/Connexin32, the gene that encodes the gap junction protein connexin32 (Cx32) cause the X-linked form of Charcot-Marie-Tooth disease (the eponym for inherited neuropathies).

Thus began one of the main lines of research in my laboratory – what are the functions of gap junctions in the myelin sheath, and how do mutations in the connexin genes disrupt these functions? Along with my colleagues and students, we have shown that Cx32 is expressed by myelinating Schwann cells and oligodendrocytes (Bergoffen et al., 1993; Scherer et al., 1995b; Kleopa et al., 2004), that there are functional gap junctions in the myelin sheath where Cx32 in localized (Balice-Gordon et al., 1998), that many connexin32 mutants cause a loss of function (Deschênes et al., 1997; Kleopa et al., 2002; Yum et al., 2002), and that oligodendrocytes and Schwann cells express other connexins that probably have overlapping functions (Altevogt et al., 2002; Kleopa et al., 2004). We have shown that Gjb1/cx32-null mice develop a demyelinating neuropathy (Scherer et al., 1998), and have made and analyzed transgenic mice that express loss-of-function mutation (R175frameship; (Abel et al., 1999), mutations that disrupt a prenylation site (C280S and S281x; (Huang et al., 2005), and a mutation that results in the retention of mutant Cx32 in the Golgi, where it appears to exert a dominant-negative effect on wild type Cx32 (R142W; (Bone Jeng et al., 2006). The current projects in my lab related to connexin biology are as follows:

  1. To determine what is important about Cx32, as compared to other connexins, by expressing various connexins and connexin chimeras in myelinating Schwann cells
  2. To determine whether the phenotypes of Cx32 mutations expressed in myelinating Schwann cells relates to their manifestations in humans. In particular, I am interested in how the clinical and subclinical CNS manifestations (Taylor et al., 2003) are produced
  3. To express various Cx32 mutants in Schwann cells with an adenovirus vector
  4. To determine the effects of recessive Cx47 mutations, which have recently been identified as the cause of Pelaeus-Merzbacher-like disease. Along with Cx29 and Cx32, Cx47 is expressed by oligodendrocytes (Menichella et al., 2003); the clinical and MRI findings in humans who lack functional Cx47 make a compelling case that this connexin plays an essential role in oligodendrocytes
  5. To determine how mutations in Cx43, which is expressed by astrocytes, affect astrocyte:oligodendrocyte coupling
  6. The role of Cx29 in myelinating glial cells

The structure and function of the myelinated axon is the other main focus of the lab. Beginning with our work on the localizations of Cx29, Cx32, and Cx47, we have examined many aspects of what might be called the “molecular architecture” of myelinated axons. We have examined the localizations of proteins associated with gap junctions, tight junctions, and adherens junctions, and how these are affected by abnormal myelination (Menichella et al., 2001; Poliak et al., 2002). Most of our effort, however, has been on understanding the repertoire of voltage-gated Na+ and K+ channels, and their localization with respect to the PNS and CNS myelin sheaths (Arroyo et al., 1999; Arroyo and Scherer, 2000; Arroyo et al., 2001; Arroyo et al., 2002; Devaux et al., 2003; Arroyo et al., 2004; Devaux et al., 2004; Devaux and Scherer, 2005). The issues here are what molecules form the myelin sheath, and what are their functional roles? The emerging evidence indicates that molecular interactions between axons and myelinating glial cells cause regional specializations in axons that are required for saltatory conduction. Further, because demyelination disrupts these regional specializations, salutatory conduction fails. The goals of this work are to understand the molecular basis for conduction, and restore conduction in demyelinating diseases such as multiple sclerosis. The current projects in this area are as follows:

  1. Determine the roles of KCNQ2, KCNQ3, and Kv3.1 in myelinated axons
  2. Detemine how demyelination and remyelination alter the various components of axons
  3. The role of the paranodal septate-like junction

In addition to these major topics, we have other projects. Dr. Sabrina Yum has a KO8 award to investigate how Cx26, Cx30, and Cx31 mutations cause hearing loss. I am interested in just about any aspect of Schwann cell biology - the role of neuregulins/erbB signaling (Cohen et al., 1992; Grinspan et al., 1996; Bermingham-McDonogh et al., 1997); their elaboration of trophic factors (Friedman et al., 1992; Scherer et al., 1993; Curtis et al., 1994; Scarlato et al., 2001; Scarlato et al., 2003); the roles of various transcription factors (Bermingham et al., 1996; Shy et al., 1996; Zorick et al., 1996; Arroyo et al., 1998; Bermingham et al., 2000; Awatramani et al., 2002; Bermingham et al., 2002); the expression of genes that may affect axonal regeneration (Burstyn-Cohen et al., 1998; Chernousov et al., 1999; Vogelezang et al., 1999; Vogelezang et al., 2001); the regulation of gene expression, particularly of genes that cause inherited demyelinating neuropathy (Scherer et al., 1995b; Scherer et al., 1995a; Street et al., 2003; Berger et al., 2004); whether the septate-like junctions are affected in an animal model of diabetic neuropathy (Brown et al., 2001).