The neuronal cell-surface molecule mitogenic for Schwann cells is a heparin-binding protein.

Abstract

The cell surface of embryonic peripheral neurons provides a mitogenic stimulus for Schwann cells. We report (a) the solubilization of this mitogenic activity from rat dorsal root ganglion neurons grown in tissue culture and (u) the solubilization and partial purification of mitogenic activity from neonatal rat brains. Extracted mitogenic activity is peripheral rather than intrinsic to the membrane, stable after extraction, and active as a mitogen in the absence of serum (the most tringent criterion defning the neuronal mitogen). We have previously provided evidence suggesting that a neuronal cellsurface heparan sulfate proteoglycan is required for expression of the neurons' mitogenic activity. We now show that mitogenic activity can be extracted from the membrane diociated from proteoglycan as assayed by its ability to bind to immobilized heparin. After dissociation, low concentrations of heparin (1 Fg/ml) inhibit the ability of the mitogen to stimulate Schwann cell division. Basic fibroblast growth factor (FGF) is weakly mitogenic for Schwann cells, but it is not present in mitogenic brain extracts (based on immunoblottig. Immunodepletion experiments with specific antibodies to FGF indicate that the mitogenic activity extracted from neurons is not a form of this heparin-binding mitogen. Acidic FGF is not mitogenic for Schwann cells and is not present in mitogenic brain extracts. We suggest that these and previous data indicate the neurite mitogen is a proteoglycan-growth factor complex that limits mitogenic activity to the axonal surface, protects mitogen against inactivation by other proteoglycans, and provides for effective presentation of mitogen to the Schwann cell.A complex series of cell-cell interactions among neurons, Schwann cells, and fibroblasts lead to the formation of the peripheral nerve. One of these interactions is the neuronstimulated proliferation of Schwann cells, first suggested by experiments in which the ratio of Schwann cells to neurons remained constant when neuronal numbers were altered (1). These in vivo observations have been extended in an in vitro system is which neurons and Schwann cells can be separated and recombined; in vitro studies demonstrate that contact with the neuronal surface causes Schwann cells to undergo a dramatic increase in both DNA synthesis and cell division (2-4). Several lines of evidence indicate that the cell surface of the neuron (rather than a released factor) carries the mitogenic stimulus. Membrane fragments from dorsal root ganglion neurons grown in tissue culture mimic the mitogenicity of whole cells, and trypsin treatment of intact neurons in culture prevents the mitogenic response of Schwann cells added to these neurons (5). Furthermore, a semipermeable collagen membrane interposed between Schwann cells and neurons in the culture dish inhibits the mitogenic response (6), and conditioned medium from neurons is not mitogenic for Schwann cells (2, 4).Recent tissue culture studies indicate that the neuronal cell-surface mitogen is associated coval...

Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2.

“…This protein is salt extractable, indicating that it is peripherally, rather than integrally, membrane bound (4). Mitogenic activity can be detected in the solubilized fraction (130,000 x g, 1 hr) of the extract, and can be inhibited by low concentrations (half-maximally at 0.5-0.7 jig/ml) of heparin (4). Further, treatment of axons with heparatinase removes the mitogenic activity from the axon (5).…”

“…Characterization of this mitogenic activity has shown it to be associated with the surface of the axon and to be sensitive to trypsin, heat, and glutaraldehyde treatment, indicating the involvement of a protein component (3). This protein is salt extractable, indicating that it is peripherally, rather than integrally, membrane bound (4). Mitogenic activity can be detected in the solubilized fraction (130,000 x g, 1 hr) of the extract, and can be inhibited by low concentrations (half-maximally at 0.5-0.7 jig/ml) of heparin (4).…”

Extracellular Matrix Molecules And Their Receptors: Functions In Neural Development

“…Other growth factors, including a mitogen for Schwann cells, also bind to heparin (e.g. Ratner et al 1988). The activity of TGF-β is regulated in two distinct ways by proteoglycans.…”

Promoting Axon Regeneration and Neurological Recovery Following Traumatic Peripheral Nerve Injuries

“…Insulin [199,200], and insulin-like growth factor-1 [220][221][222][223][224] within a bridging tube significantly increase the number of Schwann cells that migrate into the tube. Additional factors that induce Schwann cell proliferation are platelet-derived growth factor-B (PDGF-B), acidic and basic fibroblast growth factors (b-FGF and a-FGF) [225], transforming growth factor (TGF-β) [226,227] and neuregulins [224,228,229].…”