Discovery of NRG1 isoforms

Macrophages are a primary source of the growth factor Neuregulin-1 (NRG1), which has pleiotropic roles in proliferation and differentiation of the stem cell niche in different tissues, and has been implicated in gut, brain and muscle development and repair. Six isoform classes of NRG1 and over 28 protein isoforms have been previously described. Here we report a new class of NRG1, designated NRG1-VII to denote the start of this isoform class from a myeloid-specific transcriptional start site (TSS). Long-read sequencing identified up to nine different NRG1-VII transcripts that show major structural differences from one another due to use of cassette exons and alternative stop codons. Expression of NRG1-VII was confirmed in human monocytes and tissue resident macrophages. Isoform switching via cassette exon usage and alternate polyadenylation was apparent during monocyte maturation and macrophage differentiation. NRG1-VII is the major class expressed by the myeloid lineage, including tissue-resident macrophages. The size and structure of type VII isoforms suggests that they may be more diffusible than other NRG1 classes, however, the specific roles of type VII variants in tissue homeostasis and repair have not yet been determined.