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Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer.

Yee NS, Zhou W, Liang IC - Dis Model Mech (2010)

Bottom Line: The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth.TRPM7 is generally overexpressed in human pancreatic adenocarcinoma.Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. nelson-yee@uiowa.edu

ABSTRACT
Genetic analysis of pancreatic development has provided new insights into the mechanisms underlying the formation of exocrine pancreatic neoplasia. Zebrafish sweetbread (swd) mutants develop hypoplastic acini and dysmorphic ducts in the exocrine pancreas, with impeded progression of cell division cycle and of epithelial growth. Positional cloning and allelic complementation have revealed that the swd mutations affect the transient receptor potential melastatin-subfamily member 7 (trpm7) gene, which encodes a divalent cation-permeable channel with kinase activity. Supplementary Mg(2+) partially rescued the exocrine pancreatic defects of the trpm7 mutants by improving cell-cycle progression and growth and repressing the suppressor of cytokine signaling 3a (socs3a) gene. The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth. TRPM7 is generally overexpressed in human pancreatic adenocarcinoma. TRPM7-deficient cells are impaired in proliferation and arrested in the G0-G1 phases of the cell division cycle. Supplementary Mg(2+) rescued the proliferative defect of the TRPM7-deficient cells. Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

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Related in: MedlinePlus

The zebrafish swdp75fm and swdp82mf mutations cause exocrine pancreatic hypoplasia and reduced skin pigmentation. (A–F) Bright-field images of the swd mutants and wild-type (wt) larvae. Green arrows point to pigmented skin. (G–I) Exocrine pancreas (red arrows) revealed by whole-mount in situ hybridization using anti-trypsin riboprobes. (J,K) Histological transverse sections of exocrine pancreas following immunohistochemistry using anti-Cpa antibodies. Staining with DAPI was used to visualize the nuclei. The histological sections are oriented as indicated: d, dorsal; v, ventral; r, right; l, left. (L,M) Exocrine pancreas (red arrows) revealed by whole-mount in situ hybridization using anti-ptf1a riboprobes. (N,O) Sagittal histological sections of larvae. e.p., exocrine pancreas; i, intestine; l, liver. (G,L) wt larvae were grown in E3 medium supplemented with PTU, which inhibits skin pigmentation, in order to facilitate visualization of the exocrine pancreas expressing trypsin or ptf1a. Note that the larvae shown in A–O were analyzed on 5 dpf. (A–C,G–I,L–O) The larvae are positioned in the same orientation and viewed from the right lateral side. (D–F) The views are in the dorsoventral direction.
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f1-0040240: The zebrafish swdp75fm and swdp82mf mutations cause exocrine pancreatic hypoplasia and reduced skin pigmentation. (A–F) Bright-field images of the swd mutants and wild-type (wt) larvae. Green arrows point to pigmented skin. (G–I) Exocrine pancreas (red arrows) revealed by whole-mount in situ hybridization using anti-trypsin riboprobes. (J,K) Histological transverse sections of exocrine pancreas following immunohistochemistry using anti-Cpa antibodies. Staining with DAPI was used to visualize the nuclei. The histological sections are oriented as indicated: d, dorsal; v, ventral; r, right; l, left. (L,M) Exocrine pancreas (red arrows) revealed by whole-mount in situ hybridization using anti-ptf1a riboprobes. (N,O) Sagittal histological sections of larvae. e.p., exocrine pancreas; i, intestine; l, liver. (G,L) wt larvae were grown in E3 medium supplemented with PTU, which inhibits skin pigmentation, in order to facilitate visualization of the exocrine pancreas expressing trypsin or ptf1a. Note that the larvae shown in A–O were analyzed on 5 dpf. (A–C,G–I,L–O) The larvae are positioned in the same orientation and viewed from the right lateral side. (D–F) The views are in the dorsoventral direction.

Mentions: The two swd mutant lines (swdp75fm and swdp82mf) develop relatively small exocrine pancreas and have hypopigmented skin, and these two lines do not complement with each other, suggesting that they represent alleles of the same gene (Yee et al., 2005) (Fig. 1A–I). In the swd mutants at 5 days post-fertilization (dpf), the pancreatic ducts were hypomorphic with reduced branching, and the pancreatic acini were diminished in size. The mutant acinar cells expressed carboxypeptidase A (Cpa), were reduced in size and expressed relatively few zymogen granules (Yee et al., 2005) (Fig. 1J,K). The pancreatic islets of the swd mutants were indistinguishable from those of wild type (WT) as indicated by immunohistochemistry using anti-insulin and anti-glucagon antibodies (N.S.Y., unpublished).


Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer.

Yee NS, Zhou W, Liang IC - Dis Model Mech (2010)

The zebrafish swdp75fm and swdp82mf mutations cause exocrine pancreatic hypoplasia and reduced skin pigmentation. (A–F) Bright-field images of the swd mutants and wild-type (wt) larvae. Green arrows point to pigmented skin. (G–I) Exocrine pancreas (red arrows) revealed by whole-mount in situ hybridization using anti-trypsin riboprobes. (J,K) Histological transverse sections of exocrine pancreas following immunohistochemistry using anti-Cpa antibodies. Staining with DAPI was used to visualize the nuclei. The histological sections are oriented as indicated: d, dorsal; v, ventral; r, right; l, left. (L,M) Exocrine pancreas (red arrows) revealed by whole-mount in situ hybridization using anti-ptf1a riboprobes. (N,O) Sagittal histological sections of larvae. e.p., exocrine pancreas; i, intestine; l, liver. (G,L) wt larvae were grown in E3 medium supplemented with PTU, which inhibits skin pigmentation, in order to facilitate visualization of the exocrine pancreas expressing trypsin or ptf1a. Note that the larvae shown in A–O were analyzed on 5 dpf. (A–C,G–I,L–O) The larvae are positioned in the same orientation and viewed from the right lateral side. (D–F) The views are in the dorsoventral direction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3046099&req=5

f1-0040240: The zebrafish swdp75fm and swdp82mf mutations cause exocrine pancreatic hypoplasia and reduced skin pigmentation. (A–F) Bright-field images of the swd mutants and wild-type (wt) larvae. Green arrows point to pigmented skin. (G–I) Exocrine pancreas (red arrows) revealed by whole-mount in situ hybridization using anti-trypsin riboprobes. (J,K) Histological transverse sections of exocrine pancreas following immunohistochemistry using anti-Cpa antibodies. Staining with DAPI was used to visualize the nuclei. The histological sections are oriented as indicated: d, dorsal; v, ventral; r, right; l, left. (L,M) Exocrine pancreas (red arrows) revealed by whole-mount in situ hybridization using anti-ptf1a riboprobes. (N,O) Sagittal histological sections of larvae. e.p., exocrine pancreas; i, intestine; l, liver. (G,L) wt larvae were grown in E3 medium supplemented with PTU, which inhibits skin pigmentation, in order to facilitate visualization of the exocrine pancreas expressing trypsin or ptf1a. Note that the larvae shown in A–O were analyzed on 5 dpf. (A–C,G–I,L–O) The larvae are positioned in the same orientation and viewed from the right lateral side. (D–F) The views are in the dorsoventral direction.
Mentions: The two swd mutant lines (swdp75fm and swdp82mf) develop relatively small exocrine pancreas and have hypopigmented skin, and these two lines do not complement with each other, suggesting that they represent alleles of the same gene (Yee et al., 2005) (Fig. 1A–I). In the swd mutants at 5 days post-fertilization (dpf), the pancreatic ducts were hypomorphic with reduced branching, and the pancreatic acini were diminished in size. The mutant acinar cells expressed carboxypeptidase A (Cpa), were reduced in size and expressed relatively few zymogen granules (Yee et al., 2005) (Fig. 1J,K). The pancreatic islets of the swd mutants were indistinguishable from those of wild type (WT) as indicated by immunohistochemistry using anti-insulin and anti-glucagon antibodies (N.S.Y., unpublished).

Bottom Line: The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth.TRPM7 is generally overexpressed in human pancreatic adenocarcinoma.Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. nelson-yee@uiowa.edu

ABSTRACT
Genetic analysis of pancreatic development has provided new insights into the mechanisms underlying the formation of exocrine pancreatic neoplasia. Zebrafish sweetbread (swd) mutants develop hypoplastic acini and dysmorphic ducts in the exocrine pancreas, with impeded progression of cell division cycle and of epithelial growth. Positional cloning and allelic complementation have revealed that the swd mutations affect the transient receptor potential melastatin-subfamily member 7 (trpm7) gene, which encodes a divalent cation-permeable channel with kinase activity. Supplementary Mg(2+) partially rescued the exocrine pancreatic defects of the trpm7 mutants by improving cell-cycle progression and growth and repressing the suppressor of cytokine signaling 3a (socs3a) gene. The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth. TRPM7 is generally overexpressed in human pancreatic adenocarcinoma. TRPM7-deficient cells are impaired in proliferation and arrested in the G0-G1 phases of the cell division cycle. Supplementary Mg(2+) rescued the proliferative defect of the TRPM7-deficient cells. Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

Show MeSH
Related in: MedlinePlus