Investigating the sources and functions of Nerve Growth Factor in pancreatic islet development

Abstract

Sympathetic innervation is critical for the proper development and functioning of its target tissues. Sympathetic innervation of an organ is dependent on target-derived neurotrophic cues such as NGF which drive the final stages of target innervation. In the pancreas, NGF exerts indirect and direct effects on islet development and function. During development, target-derived NGF recruits sympathetic nerves to the pancreas. Loss of sympathetic innervation impairs islet architecture and functional maturation. In adult islets, NGF signalling in beta cells directly augments glucose-stimulated insulin secretion. However, the sources of NGF and their respective roles in the developing pancreas remain unclear. Here, we show that vascular mural cells are the primary source of NGF at postnatal day 7, a time period that is critical for functional maturation of islets, and sympathetic innervation. We developed a tamoxifen delivery protocol to inducibly delete NGF from mural cells during early and late postnatal development and examined the effects on pancreatic islet development and sympathetic innervation. Early NGF deletion in neonates resulted in modest defects in islet architecture and organization, and an increased number of TH+ endocrine cells. Surprisingly, sympathetic innervation to islets was not lost after NGF deletion. Late postnatal NGF deletion did not have any major effects on islet innervation. This study highlights vascular mural cells as a previously under-studied source of NGF in the developing pancreas and demonstrates their relevance in pancreatic islet development.