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A role of FRK in regulation of embryonal pancreatic beta cell formation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2007 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 270, no 1-2, 73-78 p.Article in journal (Refereed) Published
Abstract [en]

The fyn-related-kinase (FRK) is a non-receptor tyrosine kinase expressed in various tissues, and among them, is the islets of Langerhans. The role of FRK in pancreatic beta cells has been addressed by studies of knockout or FRK transgenic mice. These experiments have shown that FRK overexpression in beta cells leads to an increased susceptibility to the beta cell toxin streptozotocin and to cytotoxic cytokines, suggesting that FRK may participate in events leading to beta cell destruction. However, these mice also exhibit an increased relative beta cell volume and increased beta cell replication following partial pancreatectomy, suggesting a positive role for FRK in the regulation of beta cell number as well. To further assess the significance of FRK for beta cell replication, we studied the beta cell area and islet cell replication in FRK null mice. We currently observed that the FRK knockout mouse showed no difference in the insulin positive cell area or in the percentage of Ki67-stained proliferating islet cells at adulthood, when compared to wild-type control. In addition, adult FRK(-/-) mice performed normally when subjected to an intravenous glucose tolerance test. To elucidate whether FRK affects pancreatic beta cell number during embryogenesis and shortly after birth, pancreata were collected from FRK(-/-) mice at these stages. Histological analysis of insulin stained pancreatic sections showed that the insulin positive cell area in FRK(-/-) mice was reduced at embryonal day 15 and at birth to 31 and 70% of that of wild-type mice, respectively. FRK(-/-) pancreas weight on day 1 neonatally was similar to that of the control, indicating that the obtained results were not due to altered pancreatic growth. Taken together, these results show that FRK affects beta cell number during embryogenesis and early in life, but is probably redundant for beta cell number and function in adult animals under normal conditions.

Place, publisher, year, edition, pages
2007. Vol. 270, no 1-2, 73-78 p.
Keyword [en]
Animals, Animals, Newborn, Embryo, Mammalian/*cytology/*enzymology, Insulin-Secreting Cells/*cytology/*enzymology, Mice, src-Family Kinases/deficiency/*metabolism FRK; beta cell; development; replication; neogenesis; tyrosine kinase
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-13082DOI: 10.1016/j.mce.2007.02.009ISI: 000246920500010PubMedID: 17416457OAI: oai:DiVA.org:uu-13082DiVA: diva2:40852
Available from: 2008-01-21 Created: 2008-01-21 Last updated: 2012-12-14
In thesis
1. Frk/Shb Signalling in Pancreatic Beta-cells: Roles in Islet Function, Beta-cell Development and Survival as Implicated in Mouse Knockout Models
Open this publication in new window or tab >>Frk/Shb Signalling in Pancreatic Beta-cells: Roles in Islet Function, Beta-cell Development and Survival as Implicated in Mouse Knockout Models
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The adaptor protein Shb and the non-receptor tyrosine kinase Frk have been implicated in intracellular signalling in insulin-producing beta cells. In this thesis, knockout mice are used to further elucidate the role of Shb and Frk for beta cell number, cytokine-induced cell death, and glucose homeostasis. In addition, the effect of Shb deficiency upon tumour growth is studied in a mouse model of endogenous tumourigenesis.

Previously, overexpression of Frk has been associated with increased beta cell replication, and increased susceptibility to cytokine induced beta cell destruction. To test whether Frk has a non-redundant role in regulating beta cell mass, beta cell number in Frk-/- mice was assessed at different stages of life. The results showed that Frk is involved in regulating beta cell number during embryonal and early postnatal life, but is probably redundant in the adult.

An earlier study had suggested that Shb participates in cytokine-induced beta cell death, a model of autoimmune diabetes. To test this further, Shb-/- islets were exposed to cytokines, or to an ER-stress inducing agent. Shb knockout islets exhibited decreased cell death, and this effect appeared to be independent of NO, JNK, p38 MAP kinase, FAK and c-Abl, but may involve an augmented induction of Hsp70.

Furthermore, glucose homeostasis in Shb-/- mice was impaired, with elevated basal blood sugar concentration and reduced glucose-induced insulin secretion.

Previously Shb deficient mice had showed an impaired ability to sustain growth of implanted tumour cells, due to reduced angiogenesis. Tumour growth and angiogenesis were here assessed in an inheritable tumour model. Shb deficient mice exhibited fewer tumours, and reduced vessel density in small tumours, indicating impaired angiogenesis. However, a few large tumours developed in Shb-/- mice, suggesting that tumours can escape the angiogenic restriction caused by the absence of Shb.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 58 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 426
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
urn:nbn:se:uu:diva-89348 (URN)978-91-554-7429-4 (ISBN)
Public defence
2009-03-27, D1:419, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2009-03-05 Created: 2009-02-12 Last updated: 2009-06-10Bibliographically approved

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