Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation, and maturation of rat schwann cell precursors

Abstract

We show that beta forms of Neu differentiation factor (NDF), homologous to acetylcholine receptor-inducing activity, glial growth factor, and heregulin, prevent apoptotic death and stimulate DNA synthesis of the E14 Schwann cell precursor, an early cell in the rat Schwann cell lineage. When precursors are exposed to NDF in defined medium, they generate Schwann cells without the requirement for DNA synthesis and with a time course that is similar to that with which Schwann cells appear in embryonic nerves in vivo. Furthermore, a neuronal signal that also mediates precursor survival and maturation is blocked by the extracellular domain of the ErbB4 NDF receptor, a protein that specifically blocks the action of NDFs. These observations provide important evidence that NDF is one of the hitherto elusive neuron-glia signaling molecules long proposed to regulate development in the Schwann cell lineage.

Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation

“…Separate cultures were incubated for 4 days with no added factor (CONTROL), or with one of the following proteins, as indicated: soluble forms of ErbB-4 or ErbB-2, in the form of immunoglobulin fusion proteins (denoted IgB-4 and IgB-2, respectively), each at a concentration of 4 mg/ml, or NDFb1 14 ± 246 (100 ng/ml Figure 5b, and data not shown). To examine the possibility that endogenous NDF/neuregulin was masking the e ect of the exogenously added ligand, we attempted to block the neuron-and astroglia-derived factor by using a soluble form of ErbB-4, that we have previously characterized as an e ective antagonist of NDF (Dong et al, 1995;Chen et al, 1996). This recombinant protein, denoted IgB-4, is a fusion between the extracellular ligand binding portion of ErbB-4 and the Fc portion of immunoglobulin G 1 .…”

“…Neuregulins act as the most potent mitogens for precursor Schwann cells in vitro (Dong et al, 1995), and they reduce apoptosis of mature Schwann cells upon axotomy (Grinspan et al, 1996), probably re¯ecting a role in attaining the appropriate ratio of neurons to Schwann cells in adults (Syroid et al, 1996). An in vivo e ect on synaptic Schwann cell survival after denervation has been recently demonstrated (Trachtenberg and Thompson, 1996).…”

Overexpression of activated neu/erbB2 initiates immortalization and malignant transformation of immature Schwann cells in vitro

“…NID cells are immortalized and grow in the absence of added growth factors In vivo, normal Schwann cells require signals from axons for survival and for proliferation (Dong et al, 1995;Salzer et al, 1980;Grinspan et al, 1996). Members of the neuregulin protein family, including glial growth factor (GGF), are among these signals, and can stimulate Schwann cell proliferation and survival in vitro (Marchionni et al, 1993;Morrissey et al, 1995;Dong et al, 1995;Levi et al, 1995).…”

“…Members of the neuregulin protein family, including glial growth factor (GGF), are among these signals, and can stimulate Schwann cell proliferation and survival in vitro (Marchionni et al, 1993;Morrissey et al, 1995;Dong et al, 1995;Levi et al, 1995). Since erbB2 is phosphorylated in response to neuregulins, we tested whether NID cells, in which erbB2 is constitutively phosphorylated, grow continuously in the absence of added growth factors.…”

“…Schwann cells are the major supportive cell population in the peripheral nervous system and ensheath all peripheral axons. Axon-derived neuregulins are required for Schwann cell survival and proliferation (Marchionni et al, 1993;Morrissey et al, 1995;Dong et al, 1995;Levi et al, 1995) and function in Schwann cells by way of erbB2-erbB3 heterodimers (Cohen et al, 1992;Jin et al, 1993;Carroll et al, 1997;Vartanian et al, 1997). However, ENU-induced schwannoma cells survive and proliferate independent of neuregulins and form malignant tumors.…”