The Neuregulin 1 (NRG1) gene produces a protein that acts as a messenger within the body, guiding cell behavior. This signaling protein binds to specific ErbB receptors on cell surfaces. When NRG1 binds, it triggers events inside the cell, influencing its growth, development, and function. The NRG1 gene generates various protein versions, or isoforms, through alternative promoter usage and splicing. These isoforms are expressed uniquely across tissues and have distinct structures, enabling NRG1 to perform diverse biological roles.
The Role of NRG1 in the Nervous System
Neuregulin 1 plays a role in the central and peripheral nervous systems. It is involved in myelination, where glial cells wrap around nerve fibers to form the myelin sheath. In the peripheral nervous system, NRG1 signals Schwann cells to expand and myelinate axons; the amount of NRG1 type III on axons directly influences myelin sheath thickness. This insulation is analogous to the plastic coating on an electrical wire, ensuring rapid and efficient transmission of nerve impulses.
In the central nervous system, NRG1 contributes to myelination by influencing oligodendrocytes, the myelin-producing cells. It helps oligodendrocytes switch between myelination modes, some dependent on neuronal activity. Disruptions in this pathway can lead to decreased myelination, impacting white matter integrity. Beyond myelin, NRG1 is involved in synapse development and plasticity, fundamental to learning and memory. It aids in the formation, maturation, and strengthening of synapses, the junctions where neurons communicate.
NRG1 also guides neuronal migration, where developing neurons move to their correct positions. Alterations in NRG1 or its receptors can cause migration deficits in various neuron types, including pyramidal and GABAergic neurons. This guidance ensures that intricate neural networks are properly formed. The protein also stimulates neurite outgrowth, the extension of axons and dendrites from neurons, supporting neural connectivity.
NRG1 Function Beyond the Brain
Beyond the nervous system, NRG1 plays a role in other organ systems, especially the cardiovascular system. It is important for heart development during embryonic stages, guiding the formation of structures like trabeculae, muscular ridges in the heart chambers. This role extends into adulthood, where NRG1 contributes to maintaining normal cardiac function.
In adult hearts, NRG1 helps protect and repair cardiomyocytes (heart muscle cells). It activates signaling pathways within these cells, promoting their survival, growth, and proliferation, especially in response to stress or injury. For instance, NRG1 can shield cardiomyocytes from damage caused by certain chemotherapy drugs like doxorubicin. Endothelial cells lining the heart and blood vessels synthesize and release NRG1, supporting vascular regeneration and cardiovascular health.
NRG1 also influences mammary gland development. All four neuregulin genes, including NRG1, are expressed and play a role in mammary gland growth and formation. This broad expression highlights NRG1’s importance in diverse biological processes.
The Link Between NRG1 and Disease
Dysregulation of NRG1 signaling is linked to several human diseases. Variations in the NRG1 gene are recognized as a genetic risk factor for schizophrenia. While NRG1 variations do not directly cause the condition, they increase susceptibility, likely by affecting brain development processes like neuronal migration, myelination, and synapse formation. Some individuals with schizophrenia show abnormalities in white matter, which aligns with NRG1’s role in myelin formation.
In cancer, NRG1 has a complex, sometimes contradictory role. In some cancers, such as breast cancer, NRG1 can promote tumor growth by driving cell proliferation and inducing epithelial-mesenchymal transition, a process linked to cancer spread. This occurs through the activation of downstream signaling pathways that lead to uncontrolled cell growth. Conversely, NRG1 can have tumor-suppressive effects in other scenarios. NRG1 gene fusions, where NRG1 merges with another gene, have also been identified in various solid tumors, including non-small cell lung cancer, activating continuous signaling that fuels cancer progression.
Insufficient NRG1 signaling is implicated in heart diseases. Reduced NRG1 levels or impaired ErbB receptor activation are associated with heart failure and damage following a heart attack. A decline in NRG1 and its receptor expression has been observed in clinical data linked to the need for inotropic support and decreased ejection fraction in heart failure patients. These associations highlight how disruptions in NRG1’s functions contribute to the development and progression of various pathologies.
Therapeutic Targeting of the NRG1 Pathway
Scientists are exploring ways to manipulate the NRG1 signaling pathway for therapeutic benefit, particularly in cardiovascular diseases and cancer. One promising area involves recombinant human NRG1 (rhNRG1), a synthetic version of the protein, to treat heart failure. This recombinant protein, sometimes called Neucardin, acts directly on damaged heart muscle cells, aiming to restore their structure and function.
Recombinant NRG1 has shown beneficial effects in animal models of heart injury, including myocardial infarction and diabetic cardiomyopathy, improving cardiac function and reducing mortality. Clinical trials are ongoing to evaluate the efficacy and safety of rhNRG1 in patients with chronic heart failure, with early results demonstrating improvements in left ventricular function. This approach aims to promote cardiac repair by enhancing cardiomyocyte survival, growth, and angiogenesis.
In cancer, therapeutic strategies focus on blocking or enhancing the NRG1 pathway, depending on the cancer type and NRG1’s role. For cancers driven by NRG1 gene fusions, such as non-small cell lung cancers, therapies that block activated ErbB receptors are being investigated. For instance, pan-HER inhibitors and anti-HER monoclonal antibodies are being explored as targeted therapies for NRG1 fusion-positive tumors. This research aims to harness NRG1’s biology to develop new treatments for challenging diseases.