Neuregulins

Neuregulins are a family of epidermal growth factor-like signaling proteins that regulate development and function of the nervous system, heart, and other tissues. The family includes four ligands, NRG1 through NRG4, with multiple isoforms generated by alternative splicing and proteolytic processing. Most neuregulins are produced as membrane-bound precursors that can be cleaved to release an extracellular EGF-like domain, though some isoforms are secreted. The signaling proteins act mainly through ErbB receptor tyrosine kinases, particularly ErbB3 and ErbB4, with ErbB2 often serving as a co-receptor. Activation of these receptors triggers intracellular cascades such as PI3K-Akt and MAPK/ERK pathways, regulating cell survival, proliferation, and differentiation.

In the peripheral nervous system, neuregulin-1 type III is essential for Schwann cell development and myelination. In the central nervous system, neuregulins influence the development and maturation of cortical interneurons, modulate synaptic plasticity, and contribute to oligodendrocyte function and central myelination.

In the heart, NRG1-ErbB signaling regulates cardiomyocyte proliferation and maturation during development and contributes to cardiac repair after injury.

Genetic variation and dysregulation of neuregulin signaling have been linked to psychiatric disorders such as schizophrenia and bipolar disorder; altered NRG1 signaling has also been studied in autism. In oncology, neuregulin gene fusions and overexpression can participate in tumorigenesis, and tumors may respond to therapies targeting ErbB receptors.