SYMPATHETIC INNERVATION DURING DEVELOPMENT IS NECESSARY FOR PANCREATIC ISLET ARCHITECTURE AND FUNCTIONAL MATURATION

During development, neurons must undergo several well-characterized stages of maturation including migration, differentiation, and synapse formation. This developmental progression is critically influenced by interactions with neighboring cells such as glia, vascular cells, and targets such as the skin and muscle. In particular, it is well known that in the peripheral nervous system, target tissues secrete trophic factors such as neurotrophins which mediate neuronal survival and axon growth. However, little is understood about the reciprocal relationship neurons might have in shaping the way non-neuronal tissues develop. In recent years there have been a handful of reports that have begun to identify the diverse roles peripheral neurons may play in the developmental processes of other tissues, underscoring the importance of this emerging field of research. I identified a new role for sympathetic innervation in shaping the cellular architecture of the islets of Langerhans during development. Ablation of sympathetic neurons during development either via genetic or chemical sympathectomy leads to significant alterations in the shape and cytoarchitecture of developing islets. Islets isolated from adult mutant mice lacking sympathetic innervation showed islet-autonomous defects in insulin secretion due to a reduction in expression of the glucose transporter Glut2, as well as defects in insulin granule docking within β-cells. Overall these deficits result in glucose intolerance in these animals, due to insufficient insulin release in response to a glucose excursion. I found that the developmental interaction between sympathetic neurons and the endocrine cells of the pancreas is mediated largely through β-adrenergic signaling. Co-cultures of sympathetic neurons and dissociated islet cells revealed that β-cells preferentially migrate towards these neurons. Migration could be diminished significantly in the presence of β-adrenergic, but not α-adrenergic antagonists. Pharmacologic blockade of β-adrenergic receptors in vivo during a critical developmental window leads to impaired islet architecture, similar to the phenotypes observed with genetic or chemical sympathectomy. Conversely, treatment of mutant mice lacking sympathetic neurons during the same developmental period with a β-adrenergic agonist rescued the islet architecture and functional deficits later on in life. In contrast to the known roles of sympathetic neurons in controlling physiological responses during exercise and times of stress in adult life, my research sheds light on a previously unappreciated role for these neurons during development. I have demonstrated that during a critical peri-natal period of development, sympathetic neurons communicate to β-cells through β-adrenergic signaling to shape islet architecture, an interaction is crucial for mature islet function