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Insulin Gene Transcription: Factors Involved in Cell Type–Specific and Glucose‐Regulated Expression in Islet β Cells are Also Essential During Pancreatic Development

Roland Stein

10.1002/cphy.cp070202

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Insulin Gene Expression
2 Principal Factors Regulating Insulin Gene Transcription
2.1 C2 Element
2.2 Z‐Element Region
2.3 A Elements
2.4 C1/RIPE3b1 Element
2.5 E Element
2.6 Other Key Pancreatic Cell Transcriptional Regulators
3 Targeted Disruption of Insulin Transcriptional Activators
3.1 PDX‐1 in Pancreatic Islet and Exocrine Cell Development
3.2 Isl‐1, Pax‐6, Pax‐4, and BETA2/NeuroD in Islet Endocrine Cell Development
3.3 Other Transcription Factors Necessary for Islet Cell Development
4 Factors Regulating pdx‐1 Gene Transcription
5 New Perspectives
6 Summary
Figure 1. Figure 1.

Enhancer‐promoter region of the insulin gene. The insulin enhancer region (boxed, −340 to −91 bp) mediates pancreatic β cell–specific and glucose‐regulated transcription. The cis elements and potential positive‐and/or negative‐acting regulatory factors are shown. Sites are labeled in accordance with the nomenclature proposed by German et al. 57. Glucose regulates through the Z, A3, C1, and E1 elements. Elements Zal and RIPE3b1 correspond to the glucose‐sensitive activator gel‐shift bands obtained with Z 159 and C1 171, 179 probes; the actual regulatory factors have not been isolated. The A4 element does not appear to be conserved in the human or rat insulin II genes 48, 189.
Figure 2. Figure 2.

Structure of the PDX‐1 homeodomain transcription factor. Diagrammatic representation of PDX‐1 showing the location of the activation domain (AD) and homeodomain (HD). The conserved amino acid sequences within the activation domain required for stimulation are shown 137. The conserved pentapeptide motif necessary for Pbx‐1 binding is located between amino acids 119 and 123 (FPWMK) 135.
Figure 3. Figure 3.

BETA2/NeuroD1‐mediated neurogenic and insulin E1 element activation requires sequences important in p300/cAMP‐response element‐binding protein binding protein (CBP) co‐activator binding. Diagrammatic representation of BETA2/NeuroD1 showing the basic helix‐loop‐helix (bHLH, amino acids 100 to 156) and activation domain (AD) region [AD1 (amino acids 189 to 299) and AD2 (amino acids 300 to 355); ref. 173]. C‐terminal regions involved in p300/CBP binding in transfected cells are shown. Amino acid sequences in each BETA2/NeuroD1 construct are listed. Amino acids between 156 and 251 are deleted in Δ156 to 251. The neurogenic activity of the wild‐type and mutant BETA2/NeuroD1 constructs in injected embryos was determined by immunohistochemical staining for neural cell adhesion molecule expression; transactivation was analyzed with an insulin E‐box reporter in transfected cells. The figure summarizes the results described by Sharma et al. 173 and imply that BETA2/NeuroD1 activation of neurogenesis and insulin expression is mediated through interactions with p300/CBP.
Figure 4. Figure 4.

Model of pancreatic determination and differentiation with reference to the expression domain of insulin gene transcription factors. A: The earliest endocrine progenitor cells are characterized by expression of pdx‐1 at 8.5 days postcoitum (dpc). Initially, all cells in pancreatic buds are PDX‐1‐positive 1, 128. The first glucagon‐ (GLU) and insulin‐ (INS) expressing cells are detected at 9.5 dpc, some of which do not produce PDX‐1. This factor is also co‐expressed during development with endocrine [INS, somatostatin (SOM), pancreatic polypeptide (PP)] and exocrine [amylase (AMY) markers 64]. Expression of the other islet transcription factors appears to occur in the following order: Isl‐1 [9 dpc 3], PAX‐6 [9 dpc 161, 194], Pax‐4 [9.5 dpc 185], and BETA2/NeuroD1 [BETA2, 9.5 dpc 125]. Isl‐1, BETA2, and Pax‐6 are expressed in all islet cell types, whereas PDX‐1 and Pax‐4 are enriched in β cells. PDX‐1 is also expressed in approximately 15% of δ cells 64 and at lower levels in acinar cells 221. The parentheses around PDX‐1 denote low‐level expression. B: Approximate time period during development that the defect is manifested in null mice. The model may be oversimplistic due to the absence of precise lineage relationships between cell types.
Figure 5. Figure 5.

Hypersensitive size 1 (HSS1) is the only area of significant sequence identity within the promoter region of the mouse, human, and chicken pdx‐1 genes. Diagram of the mouse, human, and chicken promoter region: HSS1, −2560 to −1880 bp; HSS2, −1330 to −800 bp; HSS3, −260 to +180 bp. Area 1, −2694 to −2561 bp; Area 2, −2139 to −1958 bp; Area 3, −1879 to −1799 bp. The percent identity of the human and chicken sequences to that of the mouse is shown. Mouse to human, −4500/−2694, 46%; Area 1, 89%; −2435/−2201, 45%; Area 2, 78%; −1957/1880, 33%; Area 3, 84%; −1799/364, 48%; HSS3, 72%; mouse to chicken, −1731/1265, 39%; Area 1, 86%; −1101/−687, 39% [numbering is relative to the S1 transcription‐start site 170]; Area 3, 78%; −608/+1, 39% (numbering is relative to the chicken protein coding ATG codon).
Figure 6. Figure 6.

Sequence identity within area 1, area 2, and area 3 of the mouse, human, and chicken pdx‐1 genes. Highlighted sequences are conserved between species. The hepatic nuclear factor‐3β binding sites within Area 1 and Area 2 are shown. Area 1, −2694 to −2561 bp; Area 2, −2139 to −1958 bp; Area 3, −1879 to −1799 bp.


Figure 1.

Enhancer‐promoter region of the insulin gene. The insulin enhancer region (boxed, −340 to −91 bp) mediates pancreatic β cell–specific and glucose‐regulated transcription. The cis elements and potential positive‐and/or negative‐acting regulatory factors are shown. Sites are labeled in accordance with the nomenclature proposed by German et al. 57. Glucose regulates through the Z, A3, C1, and E1 elements. Elements Zal and RIPE3b1 correspond to the glucose‐sensitive activator gel‐shift bands obtained with Z 159 and C1 171, 179 probes; the actual regulatory factors have not been isolated. The A4 element does not appear to be conserved in the human or rat insulin II genes 48, 189.



Figure 2.

Structure of the PDX‐1 homeodomain transcription factor. Diagrammatic representation of PDX‐1 showing the location of the activation domain (AD) and homeodomain (HD). The conserved amino acid sequences within the activation domain required for stimulation are shown 137. The conserved pentapeptide motif necessary for Pbx‐1 binding is located between amino acids 119 and 123 (FPWMK) 135.



Figure 3.

BETA2/NeuroD1‐mediated neurogenic and insulin E1 element activation requires sequences important in p300/cAMP‐response element‐binding protein binding protein (CBP) co‐activator binding. Diagrammatic representation of BETA2/NeuroD1 showing the basic helix‐loop‐helix (bHLH, amino acids 100 to 156) and activation domain (AD) region [AD1 (amino acids 189 to 299) and AD2 (amino acids 300 to 355); ref. 173]. C‐terminal regions involved in p300/CBP binding in transfected cells are shown. Amino acid sequences in each BETA2/NeuroD1 construct are listed. Amino acids between 156 and 251 are deleted in Δ156 to 251. The neurogenic activity of the wild‐type and mutant BETA2/NeuroD1 constructs in injected embryos was determined by immunohistochemical staining for neural cell adhesion molecule expression; transactivation was analyzed with an insulin E‐box reporter in transfected cells. The figure summarizes the results described by Sharma et al. 173 and imply that BETA2/NeuroD1 activation of neurogenesis and insulin expression is mediated through interactions with p300/CBP.



Figure 4.

Model of pancreatic determination and differentiation with reference to the expression domain of insulin gene transcription factors. A: The earliest endocrine progenitor cells are characterized by expression of pdx‐1 at 8.5 days postcoitum (dpc). Initially, all cells in pancreatic buds are PDX‐1‐positive 1, 128. The first glucagon‐ (GLU) and insulin‐ (INS) expressing cells are detected at 9.5 dpc, some of which do not produce PDX‐1. This factor is also co‐expressed during development with endocrine [INS, somatostatin (SOM), pancreatic polypeptide (PP)] and exocrine [amylase (AMY) markers 64]. Expression of the other islet transcription factors appears to occur in the following order: Isl‐1 [9 dpc 3], PAX‐6 [9 dpc 161, 194], Pax‐4 [9.5 dpc 185], and BETA2/NeuroD1 [BETA2, 9.5 dpc 125]. Isl‐1, BETA2, and Pax‐6 are expressed in all islet cell types, whereas PDX‐1 and Pax‐4 are enriched in β cells. PDX‐1 is also expressed in approximately 15% of δ cells 64 and at lower levels in acinar cells 221. The parentheses around PDX‐1 denote low‐level expression. B: Approximate time period during development that the defect is manifested in null mice. The model may be oversimplistic due to the absence of precise lineage relationships between cell types.



Figure 5.

Hypersensitive size 1 (HSS1) is the only area of significant sequence identity within the promoter region of the mouse, human, and chicken pdx‐1 genes. Diagram of the mouse, human, and chicken promoter region: HSS1, −2560 to −1880 bp; HSS2, −1330 to −800 bp; HSS3, −260 to +180 bp. Area 1, −2694 to −2561 bp; Area 2, −2139 to −1958 bp; Area 3, −1879 to −1799 bp. The percent identity of the human and chicken sequences to that of the mouse is shown. Mouse to human, −4500/−2694, 46%; Area 1, 89%; −2435/−2201, 45%; Area 2, 78%; −1957/1880, 33%; Area 3, 84%; −1799/364, 48%; HSS3, 72%; mouse to chicken, −1731/1265, 39%; Area 1, 86%; −1101/−687, 39% [numbering is relative to the S1 transcription‐start site 170]; Area 3, 78%; −608/+1, 39% (numbering is relative to the chicken protein coding ATG codon).



Figure 6.

Sequence identity within area 1, area 2, and area 3 of the mouse, human, and chicken pdx‐1 genes. Highlighted sequences are conserved between species. The hepatic nuclear factor‐3β binding sites within Area 1 and Area 2 are shown. Area 1, −2694 to −2561 bp; Area 2, −2139 to −1958 bp; Area 3, −1879 to −1799 bp.

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Article Title: Insulin Gene Transcription: Factors Involved in Cell Type–Specific and Glucose‐Regulated Expression in Islet β Cells are Also Essential During Pancreatic Development
 

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Roland Stein. Insulin Gene Transcription: Factors Involved in Cell Type–Specific and Glucose‐Regulated Expression in Islet β Cells are Also Essential During Pancreatic Development. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 25-47. First published in print 2001. doi: 10.1002/cphy.cp070202