αE-Catenin Is a Positive Regulator of Pancreatic Islet Cell Lineage Differentiation
| Autor: | Giuseppe R. Diaferia, Laura Crisa, Antonio J. Jimenez-Caliani, Wendy Yang, Paolo Meda, Rudolf Pillich, Vincenzo Cirulli |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Biology Cell junction General Biochemistry Genetics and Molecular Biology Article Adherens junction 03 medical and health sciences Islets of Langerhans Mice sonic hedgehog 0302 clinical medicine Internal medicine medicine Animals α-catenin Cell Lineage Hedgehog Proteins Progenitor cell Sonic hedgehog lcsh:QH301-705.5 geography Pdx1 geography.geographical_feature_category Cell Differentiation SOX9 Transcription Factor Islet β cells Hedgehog signaling pathway 3. Good health Cell biology cell polarity 030104 developmental biology Endocrinology lcsh:Biology (General) adherens junctions Catenin biology.protein PDX1 Female pancreas development islet progenitors 030217 neurology & neurosurgery alpha Catenin Sox9 |
| Zdroj: | Cell Reports, Vol 20, Iss 6, Pp 1295-1306 (2017) Cell reports |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY The development and function of epithelia depend on the establishment and maintenance of cell-cell adhesion and intercellular junctions, which operate as mechanosensor hubs for the transduction of biochemical signals regulating cell proliferation, differentiation, survival, and regeneration. Here, we show that αE-catenin, a key component of adherens junctions, functions as a positive regulator of pancreatic islet cell lineage differentiation by repressing the sonic hedgehog pathway (SHH). Thus, deletion of αE-catenin in multipotent pancreatic progenitors resulted in (1) loss of adherens junctions, (2) constitutive activation of SHH, (3) decrease in islet cell lineage differentiation, and (4) accumulation of immature Sox9+ progenitors. Pharmacological blockade of SHH signaling in pancreatic organ cultures and in vivo rescued this defect, allowing αE-catenin-null Sox9+ pancreatic progenitors to differentiate into endocrine cells. The results uncover crucial functions of αE-catenin in pancreatic islet development and harbor significant implications for the design of β cell replacement and regeneration therapies in diabetes. Graphical abstract Jimenez-Caliani et al. examine a regulatory function for αE-catenin in the endocrine differentiation of pancreatic progenitors. Ablation of αE-catenin in multipotent Pdx1+ progenitors disrupts cell-cell adhesion and leads to constitutive activation of SHH signaling that precludes endocrine differentiation and leads to the accumulation of proliferating Sox9+ cells. Pharmacological blockade of SHH rescues the competency of αE-cateninnullSox9+ progenitors to acquire an endocrine phenotype. |
| Databáze: | OpenAIRE |
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