A functional study of all 40 Caenorhabditis elegans insulin-like peptides

Abstract

The human genome encodes 10 insulin-like genes, whereas the genome remarkably encodes 40 insulin-like genes. Knockout strategies to determine the roles of all the insulin/insulin-like peptide ligands (INS) in has been challenging due to functional redundancy. Here, we individually overexpressed each of the 40 genes pan-neuronally, and monitored multiple phenotypes including: L1 arrest life span, neuroblast divisions under L1 arrest, dauer formation, and fat accumulation, as readouts to characterize the functions of each INS Of the 40 INS peptides, we found functions for 35 INS peptides and functionally categorized each as agonists, antagonists, or of pleiotropic function. In particular, we found that 9 of 16 agonistic INS peptides shortened L1 arrest life span and promoted neuroblast divisions during L1 arrest. Our study revealed that a subset of β-class INS peptides that contain a distinct F peptide sequence are agonists. Our work is the first to categorize the structures of INS peptides and relate these structures to the functions of all 40 INS peptides Our findings will promote the study of insulin function on development, metabolism, and aging-related diseases.

Nutrient Sensing and Response Drive Developmental Progression in Caenorhabditis elegans

“…The influence of each of the 40 ILPs on developmental rate has not been measured. Overexpression of several ILPs can promote precocious cell division during starvation . However, analysis of a subset of ins gene mutants did not identify any mutants in which M cell lineage divisions were delayed and even compound mutants of ins‐4 , ins‐5 , ins‐6, ins‐7 , and daf‐28 , ILPs that prevent dauer formation, fail to delay these divisions .…”

“…Additional ILPs likely contribute to the dauer decision, as loss of many individual ILPs enhance dauer formation in sensitized genetic backgrounds or under sensitizing conditions ( Table 1 ). Based on the ability of mutants to suppress dauer formation in at least one sensitized background, several ILPs were proposed to act as antagonists, Recently, however, overexpression of ILPs using a pan‐neuronal promoter demonstrated that several ILPs could enhance one insulin‐dependent phenotype, while suppressing another, suggesting that context may also be important in determining whether ILPs act as agonists or antagonists (Table ) …”

“…daf‐28(sa191) is a dominant negative allele. Overexpression of ins genes from a pan‐neuronal promoter can influence temperature‐induced dauer formation and promote Q‐cell division . Expression patterns reported by Ritter et al: S, spermatheca; C, coelomocytes; R, rectum; HM, head muscle; VM, vulva muscle; DTC, distal tip cell; U, uterus; BM, body muscle; H, hypodermis; EM, enteric muscle; P, pharynx; BN, body neuron(s); VN, vulva neuron(s); TN, tail neuron(s); VNC, ventral nerve cord; PN, pharyngeal neuron(s); RIM, ring/intermotor neuron(s); SN, sensory neuron(s); I, intestine.…”

“…[50][51][52] Based on the ability of mutants to suppress dauer formation in at least one sensitized background, several ILPs were proposed to act as antagonists, [51,52] Recently, however, overexpression of ILPs using a pan-neuronal promoter demonstrated that several ILPs could enhance one insulin-dependent phenotype, while suppressing another, suggesting that context may also be important in determining whether ILPs act as agonists or antagonists (Table 1). [53] The influence of each of the 40 ILPs on developmental rate has not been measured. Overexpression of several ILPs can promote precocious cell division during starvation.…”

“…Overexpression of several ILPs can promote precocious cell division during starvation. [53] However, analysis of a subset of ins gene mutants did not identify any mutants in which M cell lineage divisions were delayed and even compound mutants of ins-4, ins-5, ins-6, ins-7, and daf-28, ILPs that prevent dauer formation, fail to delay these divisions. [49] These findings may suggest that distinct ILPs regulate L1 progression and dauer formation.…”