Abstract
During development, progenitor expansion, lineage allocation, and implementation of differentiation programs need to be tightly coordinated so that different cell types are generated in the correct numbers for appropriate tissue size and function. Pancreatic dysfunction results in some of the most debilitating and fatal diseases, including pancreatic cancer and diabetes. Several transcription factors regulating pancreas lineage specification have been identified, and Notch signalling has been implicated in lineage allocation, but it remains unclear how these processes are coordinated. Using a combination of genetic approaches, organotypic cultures of embryonic pancreata, and genomics, we found that sphingosine-1-phosphate (S1p), signalling through the G protein coupled receptor (GPCR) S1pr2, plays a key role in pancreas development linking lineage allocation and specification. S1pr2 signalling promotes progenitor survival as well as acinar and endocrine specification. S1pr2-mediated stabilisation of the yes-associated protein (YAP) is essential for endocrine specification, thus linking a regulator of progenitor growth with specification. YAP stabilisation and endocrine cell specification rely on Gαi subunits, revealing an unexpected specificity of selected GPCR intracellular signalling components. Finally, we found that S1pr2 signalling posttranscriptionally attenuates Notch signalling levels, thus regulating lineage allocation. Both S1pr2-mediated YAP stabilisation and Notch attenuation are necessary for the specification of the endocrine lineage. These findings identify S1p signalling as a novel key pathway coordinating cell survival, lineage allocation, and specification and linking these processes by regulating YAP levels and Notch signalling. Understanding lineage allocation and specification in the pancreas will shed light in the origins of pancreatic diseases and may suggest novel therapeutic approaches.
Highlights
The pancreas is the origin of some of the most debilitating and fatal diseases, including pancreatic cancer and diabetes
The pancreas develops from a field of progenitor cells localised in a restricted region of the embryonic endoderm
Notch attenuation is necessary for the stabilisation of the transcription factor Ngn3, which is required for the generation of endocrine cells
Summary
The pancreas is the origin of some of the most debilitating and fatal diseases, including pancreatic cancer and diabetes. Mouse reverse genetics and studies in humans have uncovered multiple transcription factors that regulate formation of the pancreatic anlagen and its subsequent expansion, branching morphogenesis, and cell specification into the endocrine, acinar, and ductal lineages [1,2]. The early pancreatic multipotent progenitor cells (MPCs) emerge at the posterior foregut region of the definitive endoderm and are defined by the expression of the transcription factors Pdx, Ptf1a, and Sox9 [4,5,6,7,8]. Decreased Notch activity at the tips of the epithelium and the antagonistic functions of Ptf1a and Nkx transcription factors delineate the acinar progenitor and endocrine/duct bipotent trunk territories [14,15,16,17]. High Notch levels divert cells to the duct fate through repression of the expression of the Ngn transcription factor
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
