Abstract：
:Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential; understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature β-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs. We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger β-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for β-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional β-cell heterogeneity and induce β-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional β-cell mass in diabetic patients.
journal_name
Naturejournal_title
Natureauthors
Bader E,Migliorini A,Gegg M,Moruzzi N,Gerdes J,Roscioni SS,Bakhti M,Brandl E,Irmler M,Beckers J,Aichler M,Feuchtinger A,Leitzinger C,Zischka H,Wang-Sattler R,Jastroch M,Tschöp M,Machicao F,Staiger H,Häring HU,Chmedoi
10.1038/nature18624subject
Has Abstractpub_date
2016-07-21 00:00:00pages
430-4issue
7612eissn
0028-0836issn
1476-4687pii
nature18624journal_volume
535pub_type
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