Afadin and RhoA Control Pancreatic Endocrine Mass via Lumen Morphogenesis

Pancreas is a vital organ responsible for digestion and blood glucose homeostasis in vertebrates. Pancreatic endocrine cells secrete hormones that regulate blood glucose levels, while exocrine cells secrete digestive enzymes. In mice, all pancreatic cell types derive from an early set of multipotent progenitors, cells of the early pancreatic bud. These progenitors complete differentiation by birth. Coincidental with differentiation, the bud epithelium forms and remodels lumens. Previous studies suggest that lumen morphogenesis is critical to endocrine and exocrine cell fate. Furthermore, recent studies show that a central network of lumens (termed core plexus) is the birthplace of most endocrine progenitors. To date, it remains unclear how pancreatic lumens form and remodel, and which aspects of lumen morphogenesis influence cell fate. Importantly, models testing the function of the central lumen network as an endocrine niche are lacking. My thesis work identifies mechanisms underlying lumen formation and remodeling, and shows that central lumen network morphogenesis impacts pancreatic endocrine mass. Through this work, I find that loss of the scaffolding protein Afadin disrupts de novo lumenogenesis and lumen continuity in the tip epithelium. Co-depletion of the actomyosin regulator RhoA and Afadin results in defects in the central lumens and arrests lumen remodeling. This arrest leads to prolonged perdurance of the central lumen network over developmental time, and expansion of the endocrine progenitor population and, eventually, endocrine mass. Thus, my thesis work uncovers essential roles of Afadin and RhoA in pancreatic central lumen morphogenesis, which subsequently determines endocrine cell mass.