Pancreas lineage allocation and specification are regulated by sphingosine-1-phosphate signalling

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.

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

“…The complex interactions of sphingolipids with nuclear gene regulation suggest close links between these pathways, but detailed understanding is missing. The ability of the sphingosine mimetic drug FTY720/fingolimod to modulate gene expression in neurons and astrocytes [38,39] is probably due in large part to the links observed between S1P receptor signaling and the activities of crucial transcription factors including NF-κB, Yin-Yang-1, or Notch [71][72][73][74][75]. However, the inhibition of class I HDACs by FTY720 / FTY720P must also be considered a potential mechanism [41,42].…”

Defining multistep cell fate decision pathways during pancreatic development at single‐cell resolution

“…A high level of Notch signaling represses Ngn3 expression but enhances ductal cell differentiation. Wnt, sphingosine-1-phosphate (S1p), and epidermal growth factor receptor (EGFR) positively regulate endocrine specification (Baumgartner et al, 2014;Lof-Ohlin et al, 2017;Serafimidis et al, 2017).…”

Protein Methyltransferase Inhibition Decreases Endocrine Specification Through the Upregulation of Aldh1b1 Expression

“…L). To confirm that Ngn3 protein stability is regulated by the proteasome also in the context of ALI cultures, we supplemented the culture medium with 1 μM of the reversible proteasome inhibitor MG132 and confirmed that this treatment increases the number of Ngn3 + cells by twofold (Supporting Information Fig. S3H, S3I).…”

“…AMI‐5 is a xanthenyl compound that inhibits the activities of protein arginine histone methyltransferases Prmt1/3/4/6 as well as histone lysine methyltransferases (HMTases) Setd7 and Dot1l in an S‐adenosylmethionine competitive manner . Prmt1 is the most strongly expressed histone methyltransferase gene during mouse embryonic pancreas secondary transition whereas Dot1l and Setd7 are also strongly expressed during that time at significant levels (Table ) . To ensure that these proteins are present in the ES‐derived PPs as well as in the developing mouse pancreas we investigated their presence by Western blot analysis.…”

“…High Notch activity diverts cells to the duct fate through the repression of Ngn3, the transcription factor that specifies endocrine cells . Sphingosine‐1‐phosphate (S1p) signaling was recently shown to enable acinar and endocrine specification through the attenuation of Notch signaling . The elucidation of the processes that maintain the progenitor status or, conversely, promote lineage specification and subsequent differentiation, is a key step toward identifying means for the maintenance and expansion of hPS derived pancreatic progenitors.…”