The autonomic nervous system is known to regulate glucose homeostasis by modulating hormone release in the adult pancreas. Pancreatic islets of Langerhans are richly innervated by sympathetic nerves of the autonomic nervous system and the onset of innervation is coincident with stages of islet growth and maturation in the developing pancreas. Yet, whether, sympathetic innervation contributes to pancreas organogenesis has not been defined so far. We recently reported that ablation of sympathetic nerves results in profound defects in the shape and cyto-architecture of islets during development in mice (Borden et. al, 2013). Sympathectomized mice exhibit reduced insulin secretion and glucose intolerance later in life. Thus, the overall goal of this proposal is to elucidate the molecular mechanisms by which sympathetic neurons promote islet formation and the acquisition of functional maturity. Based on preliminary findings, we hypothesize that the nerve-derived signal is the neurotransmitter, norepinephrine, that acts via pancreatic ?-adrenergic receptors to promote ?-cell migration and islet organization. Thus, we will determine if norepinephrine is necessary and sufficient for islet architecture by assessing islet formation i vivo in mutant mice that lack noradrenergic neurotransmission, as well as by examining the effects of norepinephrine on ?-cell migration and aggregation in vitro (Aim 1).
In Aim 2, we will identify the molecular mechanisms by which norepinephrine signaling influences islet architecture. By deep sequencing-based profiling of sympathectomized islets, we observed a dramatic down-regulation of PTTG1 (pituitary tumor-transforming gene 1), that encodes for a protein reported to have cytoskeleton-regulatory functions. Thus, we will determine if PTTG1 is a transcriptional target of norepinephrine signaling. Additionally, we will assess whether PTTG1 is an essential regulator of ?-cell migration, employing available PTTG1 knockout mice. Finally, we will elucidate the mechanisms by which nerve-derived signaling influences islet maturation by examining the effects of norepinephrine on the glucose-sensing machinery and insulin granule trafficking in ?-cells (Aim 3). The significance of our studies is that it is the first to address how the nervous system controls islet development and will also initiate a new line of research in current translational efforts to treat pancreatic dysfunction.
Diabetes mellitus results from the inability of insulin-producing ?-cells in the pancreatic islets of Langerhans to control blood glucose levels. Decreased ?-cell function or the autoimmune destruction of ?-cells results in diabetes, a major threat to human health with a global prevalence of 2.8%, a number expected to double by the year 2030. Gaining insight into factors regulating islet growth and maturation is vital to advancing our current translational efforts to enhance ?-cell function, to preserve or replace ?-cells during disease or injury. We recently reported that neuronal innervation is an essential component in the formation of pancreatic islets, and that this inductive interaction at early stages of development is critical for mature islet function in regulating glucose metabolism. The goal of this proposal is to build on these exciting initial studies to identify the molecular pathways by which sympathetic nerves instruct islet organization and the acquisition of functional maturity. These studies will address an understudied, yet highly important area of research about how the nervous system controls normal islet development and function that will also have implications for therapeutically strategies to target factors critical for the onset of pancreatic dysfunction.
