DCV Biogenesis and Maturation

The dense-core vesicle (DCV) is a specialized organelle found in neurons and endocrine cells. DCVs package and release several classes of cargo including peptide hormones, growth factors, and biogenic amines. These cargoes regulate a variety of biological processes ranging from blood-glucose homeostasis to development, function, and plasticity of the nervous system. Neuromodulators released from DCVs are particularly important in regulating our moods, emotions, and appetites. Dysfunction of these neuromodulatory pathways can lead to numerous neurological and metabolic diseases ranging from eating disorders and diabetes to schizophrenia, depression, and drug addiction. Defects in DCV biogenesis and release in pancreatic β-cells lead to reduced insulin secretion, the major cause of type II diabetes, a complex metabolic disease that affects hundreds of millions of people worldwide. Like a number of mental disorders, type II diabetes is characterized by high genetic heritability yet very few disease-causing genes have been specifically identified, a gap known as “hidden heritability.” Mutations in genes required for DCV biogenesis and release may contribute to the etiology of these diseases.

Surprisingly, very little is known about the cellular and molecular pathways that generate and sort cargoes to DCVs. DCVs are generated at the trans-Golgi network (TGN) and undergo several poorly understood maturation steps including the homotypic fusion of immature DCVs and removal of certain soluble and transmembrane cargoes. Two general models of DCV cargo sorting have been debated for more than 25 years; the ‘sorting by entry’ model proposes that sorting occurs in the TGN as DCVs bud off, and the ‘sorting by retention’ model proposes that non-DCV cargos are removed in a post-Golgi step. Experimental evidence supports both models, which are not mutually exclusive, suggesting that both mechanisms contribute to DCV biogenesis.

The general lack of understanding of DCV biogenesis is due to the fact that few molecules have been identified that function specifically in this process. To find such molecules, we performed a forward genetic screen in the nematode C. elegans for mutants defective in DCV biogenesis. Our genetic screen has already identified a number of new conserved proteins that function in DCV biogenesis. We previously characterized the functions of two novel conserved proteins, RUND-1 and CCCP-1, and their interactions with RAB-2 and its known effectors RIC-19 and TBC-8 (see graphic.) RUND-1 and CCCP-1 are conserved in mammals, but these orthologs have not been characterized. Intriguingly, the human RUND-1 ortholog maps to the same chromosomal position as a gene likely involved in autism, but this has not been considered as a candidate gene for autism because it has not been characterized. More recently, an individual with autism was found to carry a de novo nonsense mutation in the ortholog of RAB-2, so it seems likely that the newly identified genes we have discovered may be linked to a number of human neurological and metabolic disorders.