Axonal Interactions Regulate Schwann Cell Apoptosis in Developing Peripheral Nerve: Neuregulin Receptors and the Role of Neuregulins

Abstract

Programmed cell death during development resulting from the lack of appropriate survival factors has been demonstrated in both neurons and oligodendrocytes and occurs mostly in the form of apoptosis. We now demonstrate that Schwann cells in the rat sciatic nerve undergo apoptosis during early postnatal development and that the amount of apoptosis is markedly increased by axotomy. The apoptotic Schwann cells express the low-affinity nerve growth factor receptor but not myelin-related proteins, indicating that they are in the premyelinating state. Apoptosis resulting from normal development or from axotomy can be inhibited markedly by exogenous neuregulin. Consistent with this, the neuregulin receptor components erbB2 and erbB3 are expressed and phosphorylated in developing sciatic nerve. These data suggest that Schwann cell number in developing peripheral nerve is regulated by apoptosis through competition for axonally derived neuregulin.

The ERBB3 receptor in cancer and cancer gene therapy

“…Erbb2/Erbb3 heterodimer was shown to be necessary for Schwann cell differentiation. [286][287][288] Failure of migration of progenitor cells from neural crest was similarly observed in Erbb3, Erbb2 and Nrg knockout mice, implying a role for Nrg to Erbb3/Erbb2 signaling. 285,289,290 ERBB3 also has an essential role in development of the human nervous system: lethal congenital contractural syndrome 2, an autosomal recessive trait associated with atrophy of the anterior horn of the spinal cord, is caused by aberrant splicing of ERBB3.…”

Development of the Schwann cell lineage: From the neural crest to the myelinated nerve

“…Apoptosis, in the same way as proliferation, is a feature of immature Schwann cells during their normal development, as revealed by TUNEL labeling of dying cells in nerve sections (Feltri et al, 2002;Grinspan et al, 1996). Two major death signals in Schwann cells have been identified in vivo and in vitro so far.…”

Trypanosoma cruzitrans-sialidase: A potent and specific survival factor for human Schwann cells by means of phosphatidylinositol 3-kinase/Akt signaling

“…Many growth factors such as nerve growth factor and neuregulin prevent apoptosis of target cells by activating the PI3K͞Akt kinase cascade (25,26). To determine whether T. cruzi exploits such a molecular mechanism to promote Schwann-cell survival, we stimulated Schwann cells in serum-free medium with trypomastigotes and epimastigotes, the invasive and noninvasive stages of T. cruzi, respectively, to test for phosphorylation of Akt kinase at Ser-473.…”