Research

Axon-glia Communication

The formation and maintenance of myelinated nerve fibers requires the reciprocal communication between Schwann cells or oligodendrocytes with their associated axons.  We are using various molecular approaches to identify the axonal signals that enable Schwann cells and oligodendrocytes to ensheath the axons they contact and to myelinate them.

The formation and maintenance of myelinated nerve fibers requires the reciprocal communication between Schwann cells or oligodendrocytes with their underlying axons. During development, these glial cells receive specific axonal signals that control their proliferation, survival, migration and differentiation.  One of the main questions we are dealing with in the lab is what are the axonal signals that enable Schwann cells and oligodendrocytes to ensheath the axons they contact and to myelinate them?  We have used several molecular approaches, including a signal-sequence trap screen and a genetic cell ablation coupled with gene expression strategy to identify Schwann cells and oligodendrocytes cell surface proteins that may play a key role in axon-glia interaction and myelination. These approaches resulted in the identification of several novel cell recognition molecules (Opalin and Cadm4) and receptors (Gpr37), which we are currently studying using both in vitro myelination systems and various mouse models.  We are also employing unique screening methodologies we developed to identify additional axoglial signaling components.

 

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PNS and CNS myelination

Myelinating glia undergo dramatic morphological changes to generate large specialized membrane extensions that warp around the axon.  These substantial morphological changes require extensive reorganization of the cytoskeleton.  We are studying the role of cytoskeletal adaptor proteins which link extracellular signals to the intracellular machinary that contols myelin formation.

During myelination, Schwann cells and oligodendrocytes, undergo dramatic morphological changes in order to generate their large specialized membrane extensions that warp axons in multiple layers.  In the CNS for example, oligodendrocyte progenitors are settled along the fiber tracts that will be myelinated, where they differentiate into immature oligodendrocytes that send multiple filopodia which contact and ensheath axons.  Following this early, rather loose ensheathment, non-ensheathing processes are removed and spiral wrapping of the axon commences, eventually forming the compact myelin. Studies in our labs are aimed at understanding what are the intrinsic glial mechanisms required for membrane wrapping? Given that the substantial morphological changes of Schwann cells and oligodendrocytes are likely controlled by cytoskeletal reorganization, we are studying the role of several regulators of the actomyosin cytoskeleton (e.g., Ermin,  and the Neural Wiskott–Aldrich syndrome protein; N-WASP) during the different stages of myelination.  We are using proteomic and protein tagging experiments, combined with functional experiments in glia/neurons co-cultures to understand how these proteins operate in myelinating glia.

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Organization of myelinated axons

The physiology of myelinated nerves depends on the organization of the axonal membrane into distinct domains which contain differnt ion channels.  This exquisit molecular organization of the axon is controled by the overlying Schwann cells or oligodendrocyes.  We are using different molecular and genetic approaches to reveal how myelinating glia shape the membrane of the axons they wrap.

Rapid propagation of action potentials along myelinated axons depends on the high-density accumulation of voltage-gated sodium channels at regularly spaced interruptions in the myelin known as the nodes of Ranvier.  These nodal channels are separated by a specialized axoglial junction formed between the axon and myelinating glia from potassium channels that are concealed beneath the myelin sheath.  This organization, which depends on the presence of myelinating glial cells, is essential for the proper movement of the nerve impulses and its disruption results in the pathophysiological changes often seen in demyelinating human disorders.  One of the main research directions taken by our group is to understand how do myelinating glial cells control the organization of the axonal membrane they wrap? We have identified several cell adhesion molecules (Caspr, Caspr2, gliomedin and members of the Cadm family) that mediate axoglial contact and are required for the exquisite organization of the axonal membrane.  We are continuing to study their mechanism of action and are using different biochemical approaches to identify novel components of the nodes of Ranvier.  The latter is of particular interest as autoantibodies to some of the nodal proteins we identified are present in Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy.

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