Characterization of a Neuregulin-Related Gene, Don-1, That Is Highly Expressed in Restricted Regions of the Cerebellum and Hippocampus

Abstract

Members of the epidermal growth factor family of receptors have long been implicated in the pathogenesis of various tumors, and more recently, apparent roles in the developing heart and nervous system have been described. Numerous ligands that activate these receptors have been isolated. We report here on the cloning and initial characterization of a second ligand for the erbB family of receptors. This factor, which we have termed Don-1 (divergent of neuregulin 1), has structural similarity with the neuregulins. We have isolated four splice variants, two each from human and mouse, and have shown that they are capable of inducing tyrosine phosphorylation of erbB3, erbB4, and erbB2. In contrast to those of neuregulin, high levels of expression of Don-1 are restricted to the cerebellum and dentate gyrus in the adult brain and to fetal tissues.

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…EGF [7,8], transforming growth factor-α (TGF-α) [9,10], and amphiregulin [11] uniquely bind EGFR. ErbB3 binds neuregulin-1 [12][13][14][15][16] and neuregulin-2 [17][18][19][20] and uniquely binds Neuroglycan C [21]. ErbB4 is also able to bind neuregulin-1 and neuregulin-2 and uniquely binds neuregulin-3 [22], neuregulin-4 [23], and tomoregulin [24] as well.…”

The N-terminal Region of NTAK/Neuregulin-2 Isoforms Has an Inhibitory Activity on Angiogenesis

“…DISCUSSION NTAK represents at least nine alternative splicing isoforms derived from the same gene as NRG2 (7)(8)(9)(10)13), and belongs to the EGF family. In our previous study, NTAK␣ and ␤ bound directly to the ErbB3 and ErbB4 receptors, but not to ErbB1 or ErbB2 (7).…”

New branches on the neuregulin family tree

“…6 A second clue that the functions of the new neuregulins are different is that the expression of these ligands differs both spatially and temporally. [6][7][8][9]11 Both NRG1 and NRG2 mRNA are detected in the endothelial lining of the heart. NRG1 is more abundant in the ventricle than the atrium, while the converse is true for NRG2.…”

“…Like NRG1, these genes are also ligands for members of the ErbB family of receptor tyrosine kinases and their expression pattern suggests they may have important functions in the nervous system. Four different laboratories have recently published articles characterizing a gene called NRG2, 6,7 Don-1 8 or NTAK. 9 NRG2/Don-1/NTAK (referred to here as NRG2) is not an alternatively spliced variant of NRG1.…”

“…NRG2 and NRG3 are expressed at highest levels in the nervous system, although low levels of NRG2 are observed in the lung. 8 Within the CNS, the three ligands have different expression patterns. For example, expression of NRG1 in the developing cortex of E14.5 mice or postnatal day 0 rats corresponded mostly to the deeper layers (ventricular and subventricular zones) of the neuroepithelium which lines the lateral ventricles.…”