Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor.

119

Section: Requirement For Pi3k In Aria-induced Achr E Subunit Gene Expressionmentioning

confidence: 51%

ARIA/HRG regulates AChR epsilon subunit gene expression at the neuromuscular synapse via activation of phosphatidylinositol 3-kinase and Ras/MAPK pathway.

Tansey

Chu

Merlie

1996

119

“…It has previously been shown that NRG can induce growth and differentiation of epithelial cells in vitro, e.g., breast cancer cell lines respond with the production of milk proteins (Wen et al, 1992;Bacus et al, 1993;Culouscou et al, 1993). NRG stimulated the expression of a 22-kD milk protein but inhibited DIP-induced expression of [3-casein in H C l l mouse mammary epithelial cells (Marte et al, 1995).…”

Section: Discussionmentioning

confidence: 97%

Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland.

Yang

Spitzer

Meyer

et al. 1995

280

168

Abstract. We have examined the role of two mesenchymal ligands of epithelial tyrosine kinase receptors in mouse mammary gland morphogenesis. In organ cultures of mammary glands, hepatocyte growth factor (HGF, scatter factor) promoted branching of the ductal trees but inhibited the production of secretory proteins. Neuregulin (NRG, neu differentiation factor) stimulated lobulo-alveolar budding and the production of milk proteins. These functional effects are paralleled by the expression of the two factors in vivo: HGF is produced in mesenchymal cells during ductal branching in the virgin animal; NRG is expressed in the mesenchyme during lobulo-alveolar development at pregnancy. The receptors of HGF and NRG (c-met, c-erbB3, and c-erbB4), which are expressed in the epithelial cells, are not regulated. In organ culture, branching morphogenesis and lobulo-alveolar differentiation of the mammary gland could be abolished by blocking expression of endogenous HGF and NRG by the respective antisense oligonucleotides; in antisense oligonucleotide-treated glands, morphogenesis could again be induced by the addition of recombinant HGF and NRG. We thus show that two major postnatal rnorphogenic periods of mammary gland development are dependent on sequential mesenchymal-epithelial interactions mediated by HGF and NRG.ROWTH and morphogenesis of epithelia represent essential steps in the development of many eukaryotic organs. A series of developmental studies have demonstrated that growth and morphogenesis of epithelia are closely regulated by mesenchymal-epithelial interactions. These studies include transplantation and organ culture experiments, which have been carried out with various systems such as the salivary gland, the lung, the kidney, or the breast (Grobstein, 1953;Spooner and Wessells, 1970;Sax6n, 1987;Sakakura, 1991). The signaling molecules involved in mesenchymal-epithelial interactions during development are still largely unknown. Recent evidence suggests, however, that epithelial tyrosine kinase receptors and their mesenchymal ligands can take over these functions (see Birchmeier and Birchmeier, 1993; for a review).Several tyrosine kinase receptors with prevalent expression on epithelial cells have recently been characterized. The corresponding ligands are frequently synthesized by mesenchymal cells, i.e., could function in a paracrine manner (Stoker et al., 1987;Miki et al., 1991;

“…To determine whether the failure of oligodendrocyte differentiation simply reflected a reduction in the affinity of ligand binding, spinal cord explants were grown in the presence of high concentrations of exogenous NRG. Alternating spinal cord segments from embryos of each genotype were divided into two groups, one of which received 20 nM NRG (four times the reported K D of NRG for erbB4 alone; Culouscou et al, 1993) for the entire culture period, whereas the other received control vehicle alone. After 10 d, exogenous NRG-1 significantly increased the number of O1ϩ oligodendrocytes in wild-type and erbB2 ϩ/Ϫ explants (Fig.…”

Section: Excess Nrg Does Not Rescue Development Of Oligodendrocytes In the Absence Of Erbb2mentioning

confidence: 99%

The erbB2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes

Park

Miller

Krane

et al. 2001

Development of oligodendrocytes and the generation of myelin internodes within the spinal cord depends on regional signals derived from the notochord and axonally derived signals. Neuregulin 1 (NRG)-1, localized in the floor plate as well as in motor and sensory neurons, is necessary for normal oligodendrocyte development. Oligodendrocytes respond to NRGs by activating members of the erbB receptor tyrosine kinase family. Here, we show that erbB2 is not necessary for the early stages of oligodendrocyte precursor development, but is essential for proligodendroblasts to differentiate into galactosylcerebroside-positive (GalC+) oligodendrocytes. In the presence of erbB2, oligodendrocyte development is normal. In the absence of erbB2 (erbB2−/−), however, oligodendrocyte development is halted at the proligodendroblast stage with a >10-fold reduction in the number of GalC+ oligodendrocytes. ErbB2 appears to function in the transition of proligodendroblast to oligodendrocyte by transducing a terminal differentiation signal, since there is no evidence of increased oligodendrocyte death in the absence of erbB2. Furthermore, known survival signals for oligodendrocytes increase oligodendrocyte numbers in the presence of erbB2, but fail to do so in the absence of erbB2. Of the erbB2−/− oligodendrocytes that do differentiate, all fail to ensheath neurites. These data suggest that erbB2 is required for the terminal differentiation of oligodendrocytes and for development of myelin.