Ioannis Serafimidis and colleagues recently published a paper in PLOS Biology. In this study, the authors identified and characterised a novel signalling pathway involved in pancreatic lineage allocation and specification.
The pancreas develops from a field of progenitor cells that actively proliferate and eventually differentiate to generate the three distinct lineages comprising the endocrine (which include insulin-producing β cells), acinar, and ductal cells. The molecular pathways implicated in the early generation of pancreas progenitors are well understood, however, the signals that regulate subsequent cell fate decisions to generate the three lineages remain largely unknown. In this study, the authors show that a phospholipid, sphingosine-1-phosphate (S1p), generated by the progenitor cells themselves, acts as a signal necessary to define the acinar and endocrine lineages. In the absence of S1p only duct cells are generated and the survival of pancreas progenitors is compromised. The function of this signalling pathway in the generation of the endocrine cells is two-fold: Firstly, it stabilises yes-associated protein (YAP), a transcriptional gene coactivator shown here to be necessary for the activation of the endocrine specification program. Secondly, it attenuates Notch signalling, allowing the generation of endocrine and acinar cells. Notch attenuation is necessary for the stabilisation of the transcription factor Ngn3, which is required for the generation of endocrine cells.
The authors conclude that S1p acts as an autocrine signal regulating YAP stabilisation and Notch attenuation to mediate pancreas specification. Understanding lineage allocation and specification in the pancreas will shed light on the origins of pancreatic diseases and may suggest novel therapeutic approaches.
Serafimidis I, Rodriguez-Aznar E, Lesche M, Yoshioka K, Takuwa Y, Dahl A, Pan D, Gavalas A.
Pancreas lineage allocation and specification are regulated by sphingosine-1-phosphate signalling.
PLOS Biology 15(3): e2000949. doi: 10.1371/journal.pbio.2000949