Mechanisms coupling growth and metabolism are conserved in Drosophila and mammals. In metazoans, such coupling is achieved across tissue scales through the regulated secretion of chemical messengers such as insulin that control the metabolism and growth of cells. Although the regulated secretion of Insulin like peptide (dILP) is key to normal growth and metabolism in Drosophila, the sub-cellular mechanisms that regulate dILP release remain poorly understood. We find that reduced function of the only protein kinase D in Drosophila (dPKD) results in delayed larval growth and development associated with abnormal sugar and lipid metabolism, reduced insulin signalling and accumulation of dILP2 in the neurosecretory IPCs of the larval brain. These phenotypes are rescued by tissue-selective reconstitution of dPKD in the neurosecretory cells of dPKD. Selective downregulation of dPKD activity in the neurosecretory IPCs phenocopies the growth defects, metabolic abnormalities and dILP2 accumulation seen in dPKD. Thus, dPKD mediated secretion of dILP2 from neurosecretory cells during development is necessary for normal larval growth.
To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
Lineage tracing using genetically engineered mouse models is an essential tool for investigating cell-fate decisions of progenitor cells and biology of mature cell types, with relevance to physiology and disease progression. To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We isolated duct cells within the murine pancreas using a Dolichos biflorus agglutinin (DBA) lectin sorting strategy that labels all pancreatic duct cell types. Our data suggested the substructure of murine pancreatic duct cells is compartmentalized into three subpopulations. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify SPP1 as a regulator of this fate decision as well as human duct cell de-differentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for Geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
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