Abstract
ABSTRACTThe three-dimensional architecture of the pancreatic islet is integral to beta cell function, but the process of islet formation remains poorly understood due to the difficulties of imaging internal organs with cellular resolution. Within transparent zebrafish larvae, the developing pancreas is relatively superficial and thus amenable to live imaging approaches. We performed in vivo time-lapse and longitudinal imaging studies to follow islet development, visualizing both naturally occurring islet cells and cells arising with an accelerated timecourse following an induction approach. These studies revealed previously unappreciated fine dynamic protrusions projecting between neighboring and distant endocrine cells. Using pharmacological compound and toxin interference approaches, and single-cell analysis of morphology and cell dynamics, we determined that endocrine cell motility is regulated by phosphoinositide 3-kinase (PI3K) and G-protein-coupled receptor (GPCR) signaling. Linking cell dynamics to islet formation, perturbation of protrusion formation disrupted endocrine cell coalescence, and correlated with decreased islet cell differentiation. These studies identified novel cell behaviors contributing to islet morphogenesis, and suggest a model in which dynamic exploratory filopodia establish cell-cell contacts that subsequently promote cell clustering.
Highlights
Pancreatic islets are clusters of endocrine cells that produce hormones important for regulation of glucose homeostasis
Given the similar impact of phosphoinositide 3-kinase (PI3K) inhibition and G-protein-coupled receptor (GPCR) blockade on islet cell aggregation, we examined whether protrusion formation and cell motility were affected in endocrine cells of pertussis toxin (PTX)-expressing larvae. hsp70:LifeActTom-PTX;mnx1:memEGFP embryos induced by Notch inhibition were heat shocked at 7 dpf, examined 4-6 h later by time-lapse microscopy
In this work, we show that endocrine cells form highly dynamic fine protrusions, and we provide evidence that this protrusion formation is important for islet assembly
Summary
Pancreatic islets are clusters of endocrine cells that produce hormones important for regulation of glucose homeostasis. The ‘primary transition’ is characterized by epithelial budding and formation of early primitive endocrine cells, while the definitive endocrine cells arise during a second wave of cell expansion and differentiation called the. They show analogous behavior to their mammalian counterparts, as they emerge from a branching ductal network and cluster into polyclonal islets (Beer et al, 2016; Ninov et al, 2013)
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