Journal
EMBO JOURNAL
Volume 38, Issue 8, Pages -Publisher
WILEY
DOI: 10.15252/embj.2018100164
Keywords
cell fate choice; fate map; MAPK; ERK; pancreatic lineage; single-cell RNA-seq
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Funding
- National Basic Research Program of China (973 Program) [2015CB942800]
- National Natural Science Foundation of China [31521004, 31471358, 31522036, 91753138]
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The generation of terminally differentiated cell lineages during organogenesis requires multiple, coordinated cell fate choice steps. However, this process has not been clearly delineated, especially in complex solid organs such as the pancreas. Here, we performed single-cell RNA-sequencing in pancreatic cells sorted from multiple genetically modified reporter mouse strains at embryonic stages E9.5-E17.5. We deciphered the developmental trajectories and regulatory strategies of the exocrine and endocrine pancreatic lineages as well as intermediate progenitor populations along the developmental pathways. Notably, we discovered previously undefined programs representing the earliest events in islet alpha- and beta-cell lineage allocation as well as the developmental pathway of the first wave of alpha-cell generation. Furthermore, we demonstrated that repressing ERK pathway activity is essential for inducing both alpha- and beta-lineage differentiation. This study provides key insights into the regulatory mechanisms underlying cell fate choice and stepwise cell fate commitment and can be used as a resource to guide the induction of functional islet lineage cells from stem cells invitro.
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