News and Publications

ErbB Receptors and Ligands in the Nervous System

C. Lai, J. Weber, N. Yu, E. Fung, W. Cui

Research in this laboratory focuses on understanding the signaling mechanisms that underlie the establishment and maintenance of mature neuronal phenotypes. We are studying the role played by one class of signal transduction molecules, the protein-tyrosine kinases. Although they are best known for their role in cell growth and proliferation, we wish to determine possible functions for these receptors in postmitotic neurons in the brain in adult rats. We focus on the ErbB4 receptor and its ligands, neuregulin-1, neuregulin-2, and neuregulin-3.

ErbB4 is the fourth member of the epidermal growth factor receptor subfamily of molecules. Along with ErbB3, ErbB4 serves as a receptor for neuregulin-1, a family of molecules that arise via alternative splicing from a single gene. ErbB2 and the receptor for epidermal growth factor also participate in neuregulin signaling as a result of receptor heterodimerization. Neuregulin-1 was first cloned as "heregulin" and "neu differentiation factor" and was initially thought to be a ligand for ErbB2, which is overexpressed in about 25% of women with breast cancer. Neuregulin-1 has also been studied as the "glial growth factor," which acts as a Schwann cell mitogen, and as "ARIA" (acetylcholine receptor inducing activity), a regulator of the expression of acetylcholine receptors.

In the peripheral nervous system, ErbB4 helps regulate glial proliferation and acts as a signaling molecule at the neuromuscular junction. In the mature CNS, ErbB4 is expressed in cerebellar granule cells and in a subset of cells that also express the neurotransmitter -aminobutyric acid. ErbB4 is critical in cardiac development; mice lacking ErbB4 die as a result of a failure in ventricular trabeculation. These mice also have neural defects, including apparent targeting errors of several cranial ganglia.

We have identified neuregulin-2, a novel neuregulin-1--like molecule encoded by a distinct gene. Like neuregulin-1, neuregulin-2 also binds to ErbB3 and ErbB4, although it appears to signal distinctly, perhaps by activating different receptor heterodimers. Neuregulin-1 and neuregulin-2 are largely expressed in nonoverlapping sets of cells in the brain in adult rats. Neuregulin-2 is primarily found in granule cells in the cerebellum, hippocampus, and olfactory bulb. In the developing heart, neuregulin-2 is mainly found in the atrium, whereas neuregulin-1 is predominantly found in the ventricle. These patterns suggest that neuregulin-2 and neuregulin-1 have distinct functions. We are also studying the recently described neuregulin-3 and are determining if a neuregulin-like molecule discovered in the expressed sequence tag database encodes a functional neuregulin.