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Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan
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Abstract |
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 Top Abstract IntroductionResultsDiscussionExperimental proceduresReferences |
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Introduction |
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It has been shown that the development of the digestive organs is antagonistically regulated by basic helix–loop–helix (bHLH) activator and repressor genes (Jensen 2004; Radtke & Clevers 2005; Crosnier et al. 2006). For example, in the developing pancreas, the bHLH activator genes Ptf1a and Neurogenin3 (Ngn3) promote specification of exocrine and endocrine cells, respectively (Krapp et al. 1998; Gradwohl et al. 2000; Schwitzgebel et al. 2000; Kawaguchi et al. 2002), while the bHLH repressor gene Hes1 maintains progenitors by repressing Ptf1a and Ngn3 expression (Jensen et al. 2000; Lee et al. 2001; Fukuda et al. 2006). Similarly, in the small intestine, the bHLH activator gene Math1 promotes development of goblet, endocrine and Paneth cells (Akazawa et al. 1995; Yang et al. 2001), while Hes1 maintains stem cells by repressing Math1 (Jensen et al. 2000; Fre et al. 2005; van Es et al. 2005). In the stomach, Ngn3 not only promotes formation of subsets of endocrine cells but also regulates maintenance of gastric versus intestinal epithelial cell identity (Jenny et al. 2002; Lee et al. 2002), while Hes1 inhibits endocrine cell differentiation (Jensen et al. 2000). Although Ngn3 is expressed by progenitors for all principal gastric endocrine cell types, only gastrin-, glucagon- and somatostatin-producing cells are severely reduced in number in Ngn3-null mice, while the other types of endocrine cells are still formed (Jenny et al. 2002; Lee et al. 2002). These results raised the possibility that another bHLH gene is involved in the formation of Ngn3-independent endocrine cells. One of the candidate genes is the bHLH activator mammalian achaete-scute homologue (Mash1), because it has been shown that this gene is expressed in the developing stomach (Jensen et al. 2000).
Here, we show that Mash1 is highly expressed in the epithelium of the developing glandular stomach and that in Mash1-null mice, almost all gastric endocrine cells are missing, although Ngn3 expression is not affected. Thus, Ngn3 alone is not sufficient but Mash1 is additionally required for these endocrine cells. These results indicate that there are at least two groups of gastric endocrine cells, the cells dependent on both Mash1 and Ngn3 and those on Mash1 alone.
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Results |
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To determine the expression patterns of Mash1 in the developing stomach, in situ hybridization was performed with mouse embryos. At embryonic day 12.5 (E12.5), Mash1 is highly expressed by differentiating enteric neurons in the mesenchyme of the stomach (Fig. 1A), but the expression does not yet occur in the gastric epithelium (Fig. 1A, arrowheads). At E14.5 and E16.5, Mash1 is expressed in the epithelium of the glandular stomach (Fig. 1B,C, arrowheads), in addition to enteric neurons. Mash1 is also expressed in the epithelium of the adult glandular stomach, although the number of Mash1-expressing cells is significantly reduced, compared to the embryonic stomach (Fig. 1D, arrowheads). Ngn3 is expressed by some cells in the epithelium at E12.5 (Fig. 1E) and Ngn3-expressing cells are increased in number at E14.5 and E16.5 (Fig. 1F,G). It is also expressed in the adult stomach, although the number of Ngn3-expressing cells is significantly reduced, compared to the embryonic stomach (Fig. 1H, arrowhead). Expression of another bHLH gene, NeuroD, is not observed at E12.5 (Fig. 1I) but occurs in the epithelium of the glandular stomach at E14.5 and E16.5 (Fig. 1J,K). These bHLH genes are never expressed in the forestomach epithelium (data not shown). These results suggest that Mash1 is involved in the differentiation of the glandular stomach, like Ngn3 and NeuroD. Because there are more Mash1-expressing cells than Ngn3- or NeuroD-expressing cells (Fig. 1), it is likely that Mash1 is more widely involved in the differentiation of gastric epithelial cells. Expression of the bHLH genes Ngn1, Ngn2, Math1 and Math6 was also examined but was not detectable in the stomach (data not shown).
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To identify the roles of Mash1 in the development of the stomach, we examined Mash1-null mice. These mutant mice were found to have smaller stomachs than the control (Fig. 2A,B). However, the wall of the Mash1(–/–) glandular stomach is much thicker than that of the control (Fig. 2C–F). The mutant wall has a deeper fold structure. Furthermore, the forestomach epithelium (cytokeratin 14+) of Mash1(–/–) mice is villous (Fig. 2J), while that of the control is rather flat (Fig. 2I). Cell proliferation (phosphorylated histone H3-positive cells) and death (TUNEL-positive cells) are not significantly affected in the Mash1-null stomach (data not shown). However, the cell number counted in several representative sections revealed a 1.5-fold increase in the Mash1(–/–) stomach compared to the control (n = 4), suggesting that the structural defects of the Mash1-null stomach could be due to abnormal cell proliferation or death, in addition to abnormal cytoarchitecture or cell composition.
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Defects of neuroendocrine cells in Mash1-null glandular stomach
To identify the roles of Mash1 in the development of the stomach epithelium, we next examined formation of four principal cell types in Mash1-null mice. At E18.5, chromogranin A, a general neuroendocrine cell marker, is expressed in the glandular stomach of Mash1(+/–) mice (Fig. 3A,C). In contrast, only very few chromogranin A-positive cells are detectable in the Mash1(–/–) stomach (Fig. 3B,D, arrow). These results suggest that almost all gastric endocrine cells are missing in the absence of Mash1. The defects of neuroendocrine cells seem to be specific to the stomach, because there are many chromogranin A-positive cells in the small intestine of Mash1(–/–) mice (Fig. 3F), as in the control mice (Fig. 3E). In agreement with the result, there are almost no Mash1-expressing cells in the small intestine (data not shown). Intrinsic factor, a marker of chief cells in mice, is widely expressed in the glandular stomach of Mash1(–/–) mice (Fig. 3H), as in the control mice (Fig. 3G). In addition, parietal cells (Fig. 3I,J, H+/K+-ATPase+) and pit cells (Fig. 3K,L, PAS/Alcian blue+, arrowheads) are formed in Mash1(–/–) mice, as in the control. Thus, in the Mash1-null stomach, three principal cell types, chief, parietal and pit cells are formed, whereas only neuroendocrine cells are mostly missing.
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We next examined whether expression of Ngn3 and NeuroD is affected in the absence of Mash1. Ngn3 expression is not significantly affected in the Mash1-null stomach at E14.5 or E18.5 (Fig. 6A–D). Furthermore, expression of NeuroD, which is regulated by Ngn3 in the intestine (Jenny et al. 2002), is not significantly affected in the Mash1-null stomach (Fig. 6E,F). These results indicate that expression of both Ngn3 and NeuroD is not regulated by Mash1 in the stomach.
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It was previously shown that neuroendocrine cell development is accelerated in the absence of Hes1 (Jensen et al. 2000; Kageyama et al. 2007). We thus examined whether Mash1 expression is up-regulated in the Hes1-null stomach. As expected, Mash1-expressing cells are significantly increased in number in the epithelium of the Hes1-null stomach (Fig. 7B), compared to the control (Fig. 7A). Similarly, Ngn3- and NeuroD-expressing cells are significantly increased in the Hes1-null stomach (Fig. 7D,F), compared to the control (Fig. 7C,E). Thus, Hes1 negatively regulates neuroendocrine cell development by repressing bHLH genes, such as Mash1 and Ngn3, in the stomach.
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Discussion |
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We here show that in the Mash1-null stomach, neuroendocrine cells are mostly missing, while chief, parietal and pit cells are formed. It was previously shown that gastrin-, glucagon- and somatostatin-producing cells are missing in the Ngn3-null stomach, while other neuroendocrine cells are formed (Jenny et al. 2002; Lee et al. 2002). These results indicate that Mash1 is more widely involved in the specification of neuroendocrine cell fates than Ngn3 in the stomach. Because Mash1-null mice die before the formation of histamine-producing cells, the most abundant neuroendocrine cells in the stomach, it was not possible to determine whether differentiation of these cells is affected in Mash1-null mice. However, because there are very few cells positive for the pan-neuroendocrine marker chromogranin A, it is most likely that histamine-producing cells are also mostly missing in Mash1-null stomach. Based on these results, gastric neuroendocrine cells are classified into two groups: cells dependent on both Mash1 and Ngn3 and those on Mash1 alone. It is thus possible that a combination of Mash1 and Ngn3 promotes specification of gastrin-, glucagon- and somatostatin-producing cells, while Mash1 alone leads to specification of the other neuroendocrine subpopulations. We found that Mash1 and Ngn3 are co-expressed by only subsets of cells but not by the majority, raising the possibility that Mash1 and Ngn3 function at overlapping but distinct stages of development of gastrin-, glucagon- and somatostatin-producing cells. In Mash1-null stomach, we still observed a very few ghrelin-producing cells, although they are significantly reduced in number. Because Ngn3 and NeuroD expression is not affected by Mash1 mutation, it is possible that the formation of subsets of ghrelin-producing cells could be regulated by Ngn3 and/or NeuroD.
Interestingly, Ngn3 is expressed by both neuroendocrine and non-neuroendocrine progenitors (Schonhoff et al. 2004). Because there are abundant Mash1-expressing cells in the epithelium of the glandular stomach, it is possible that Mash1 is also expressed by non-neuroendocrine cells. However, this possibility was not confirmed yet, because Mash1 is not co-expressed with the cell-type markers that we tested. We also tried the lineage tracing of Mash1-expressing cells by crossing Mash1-cre mice (kindly provided by Dr Jane Johnson, Battiste et al. 2007) and Rosa26 reporter mice, but we did not find any labeled cells in the epithelium of the stomach, probably because the Mash1 promoter in this cre line does not contain the stomach-specific enhancer (our unpublished data). Thus, it remains to be determined whether or not Mash1 expression is specific to neuroendocrine progenitors.
The Mash1-null stomach has a smaller size but a thicker wall than the control. Apparently, cell death and proliferation are not significantly affected in the mutant stomach. This phenotype is somewhat similar to hypertrophic gastropathy, although it remains to be determined whether Mash1 is involved in this disease. The mechanism of how these defects occur in the absence of Mash1 is currently unknown, but the loss of neuroendocrine cells could lead to such structural defects in the Mash1-null stomach, because neuroendocrine cells are known to regulate development of other cells. Because Mash1 is required for the development of enteric neurons (Guillemot et al. 1993; Blaugrund et al. 1996), defects of such neurons could also lead to the structural abnormality of the stomach.
Involvement of other bHLH genes in development of gastric neuroendocrine cells
Because Ngn3 and NeuroD expression is not affected in the Mash1-null stomach, Ngn3 and NeuroD are regulated independently of Mash1 in the stomach. This is the contrast to the intestine, which seems to have a bHLH gene cascade of Math1
Ngn3NeuroD (Jenny et al. 2002). It remains to be determined how Mash1 and Ngn3 are regulated in the stomach.
We also show that in the Hes1-null stomach, Mash1 and Ngn3 are significantly up-regulated, indicating that Hes1 inhibits neuroendocrine cell formation by repressing Mash1 and Ngn3. This is reminiscent of the bHLH gene networks in neural development (Kageyama et al. 2005, 2007). In the developing nervous system, Hes1 not only represses transcription of Mash1 by directly binding to its promoter (Chen et al. 1997) but also inhibits Mash1 activity by forming a non-DNA-binding heterodimer (Sasai et al. 1992), thereby maintaining neural stem cells (Hatakeyama et al. 2004). We thus speculate that the same bHLH gene networks function in the neuroendocrine cell formation and that Hes1 maintains epithelial progenitors in the stomach.
Hes1 is also important in inhibiting the formation of the ectopic pancreas. We previously reported that in the absence of Hes1, the ectopic pancreas is formed in the stomach as well as in the intestine and the common bile duct by induction of Ptf1a and Ngn3 expression (Sumazaki et al. 2004; Fukuda et al. 2006). In the ectopic pancreas, both pancreatic exocrine (acinar cells) and endocrine cells, such as insulin-producing β cells, are formed. Ptf1a regulates commitment of pancreas and specification of exocrine cells and Ngn3 regulates the specification of endocrine cells, whereas Hes1 inhibits each step by antagonizing Ptf1a and Ngn3. Thus, multiple bHLH genes are involved in the proper development of the stomach at various levels.
Different bHLH genes regulate endocrine cell development in different organs
Apparently, the roles of Mash1 in endocrine cell development are specific to the stomach, because there is no significant defect in other digestive organs including the pancreas (data not shown). In the intestine, Math1 is essential for formation of endocrine cells as well as goblet and Paneth cells (Yang et al. 2001), while Ngn3 is required for all types of endocrine cells in the pancreas (Gradwohl et al. 2000). Thus, different bHLH genes are responsible for endocrine cell development in different organs. However, it remains to be determined whether these bHLH genes are involved in organ specificity or interchangeable with each other. In the Hes1-null stomach, Ngn3 is up-regulated, but only subsets of the Ngn3-expressing cells become pancreatic endocrine cells, while most others are gastric endocrine cells (Fukuda et al. 2006), suggesting that Ngn3 alone cannot specify the pancreatic cell fates. Thus, it is likely that another factor is required for organ specificity. In accordance with this notion, in addition to Ngn3, the homeodomain genes Pdx1 and Pax4 are required for the specification of pancreatic β cells (Jonsson et al. 1994; Offield et al. 1996; Sosa-Pineda et al. 1997). Thus, it is likely that combinations of bHLH genes and other types of transcription factors, such as homeodomain factors, are important for the generation of tissue-specific endocrine cells (Jensen 2004). Identification of such transcription factor codes will be useful to regenerate specific endocrine cell types.
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Experimental procedures |
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All animals used in this study were maintained and handled according to the protocols approved by Kyoto University. Generation of Mash1-mutant and Hes1-mutant mice were reported previously (Guillemot et al. 1993; Ishibashi et al. 1995). Genotyping of Mash1-mutant mice was performed by PCR using the following primers: Mash1 sense, 5'-ACGACTTGAACTCTATGGCGGGTTCTC-3'; Mash1 wild-type anti-sense, 5'-GCCACTCTCAGGGGCCAAGACTGAAGTTAA-3'; Mash1 mutant anti-sense, 5'-AAATTAAGGGCCAGCTCATTCCTCCACTCA-3'. Genotyping of Hes1-mutant mice was determined by PCR as described previously (Hirata et al. 2001) with the following primers: Hes1 sense; 5'-ATATATAGAGGCCGCCAGGGCCTGCGGGATC-3', Hes1 wild-type anti-sense; 5'-CGCAGGTACTGTCTTACCTTTCTGTGCTCAGAGGCC-3', Hes1 mutant anti-sense; 5'-CGCTTCCATTGCTCAGCGGTGCTGTCCATC-3'.
In situ hybridization
RNA in situ hybridization on frozen and paraffin sections was performed using digoxigenin-labeled RNA probes as described previously (Ohsawa et al. 2005). Tissues were dissected out and fixed in 4% paraformaldehyde in PBS at 4 ºC overnight and processed as described above. RNA probes used were Mash1, Ngn3, NeuroD and Ghrelin probes.
Immunohistochemistry
Tissues were dissected out in ice-cold PBS and fixed in 4% paraformaldehyde in phosphate-buffered saline (PBS) at 4 ºC for 1 h. Then, they were rinsed in ice-cold PBS 3 times, equilibrated in 20% sucrose overnight at 4 ºC and mounted in OCT compound. Samples were cut at 16 µm thickness and blocked in 5% normal goat serum and 0.1% Triton X-100 at room temperature for 1 h. Then, sections were incubated with primary antibodies diluted in 1% normal goat serum and 0.1% Triton X-100 overnight at 4 ºC. They were next washed 3 times in PBS and incubated with secondary antibodies at room temperature for 2 h. Primary antibodies used in this study were as follows: rabbit anti-chromogranin A (1 : 100, DiaSorin, Stillwater, MN), rabbit anti-gastrin (1 : 50, YLEM, Avezzano, Italy), rabbit anti-glucagon (1 : 100, Zymed, San Francisco, CA), rabbit anti-serotonin (1 : 100, Zymed), rabbit anti-somatostatin (1 : 100, Zymed), rabbit anti-Intrinsic factor (1 : 2000, Fitzgerald, Concord, MA), rabbit anti-cytokeratin 14 (1 : 2000, Covance, Denver, PA), mouse anti-hydrogen potassium ATPase (H+/K+-ATPase) (1 : 1000, Abcam, Cambridge, UK), mouse anti-βIII tubulin (Tuj1) (1 : 500, Covance), mouse anti-smooth muscle actin (SMA) (1 : 300, SIGMA, St. Louis, MO) and mouse anti-phosphorylated histone H3 (1 : 200, SIGMA). Alexa 488 or Alexa 594-conjugated anti-mouse or rabbit IgG (1 : 200, Molecular Probes, Eugene, OR) was used as a secondary antibody.
Double staining of in situ hybridization and immunohistochemistry
In situ hybridization was first performed as described above and signal was visualized by FastRed. Then, immunohistochemistry was performed as described above.
TUNEL assay and PAS/Alcian blue staining
TUNEL assay was performed using a kit (Invitrogen, Carlsbad, CA). PAS/Alcian Blue staining was performed by standard procedures. Briefly, sections prepared as described above were rinsed in PBS 3 times and incubated in the Alcian Blue solution at room temperature for 5 min and washed in running water. Sections were next incubated in periodic acid at room temperature for 10 min, washed in running water and incubated in Schiff's reagent at room temperature for 15 min. Sections were counter-stained with hematoxylin solution.
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Acknowledgements |
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Footnotes |
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* Correspondence: E-mail: rkageyam{at}virus.kyoto-u.ac.jp
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References |
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Battiste, J., Helms, A.W., Kim, E.J., Savage, T.K., Lagace, D.C., Mandyam, C.D., Eisch, A.J., Miyoshi, G. & Johnson, J.E. (2007) Ascl1 defines sequentially generated lineage-restricted neuronal and oligodendrocyte precursor cells in the spinal cord. Development 134, 285–293.
Blaugrund, E., Pham, T.D., Tennyson, V.M., lo, L., Sommer, L., Anderson, D.J. & Gershon, M.D. (1996) Distinct subpopulations of enteric neuronal progenitors defined by time of development, sympathoadrenal markers and Mash-1-dependence. Development 122, 309–320.[Abstract]
Chen, H., Thiagalingam, A., Chopra, H., Borges, M.W., Feder, J.N., Nelkin, B.D., Baylin, S.B. & Ball, D.W. (1997) Conservation of the Drosophila lateral inhibition pathway in human lung cancer: A hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression. Proc. Natl. Acad. Sci. USA 94, 5355–5360.
Crosnier, C., Stamataki, D. & Lewis, J. (2006) Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nat. Rev. Genet. 7, 349–359.[CrossRef][Medline]
Dockray, G.J. (1999) Gastrin and gastric epithelial physiology. J. Physiol. 518.2, 315–324.
Fre, S., Huyghe, M., Mourikis, P., Robine, S., Louvard, D. & Artavanis-Tsakonas, S. (2005) Notch signals control the fate of immature progenitor cells in the intestine. Nature 435, 964–968.[CrossRef][Medline]
Fukuda, A., Kawaguchi, Y., Furuyama, K., Kodama, S., Horiguchi, M., Kuhara, T., Koizumi, M., Boyer, D.F., Fujimoto, K., Doi, R., Kageyama, R., Wright, C.V. & Chiba, T. (2006) Ectopic pancreas formation in Hes1-knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas. J. Clin. Invest. 116, 1484–1493.[CrossRef][Medline]
Gradwohl, G., Dierich, A., LeMeur, M. & Guillemot, F. (2000) Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc. Natl. Acad. Sci. USA 97, 1607–1611.
Guillemot, F., Lo, L.C., Johnson, J.E., Auerbach, A., Anderson, D.J. & Joyner, A.L. (1993) Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell 75, 463–476.[CrossRef][Medline]
Hatakeyama, J., Bessho, Y., Katoh, K., Ookawara, S., Fujioka, M., Guillemot, F. & Kageyama, R. (2004) Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131, 5539–5550.
Hirata, H., Tomita, K., Bessho, Y. & Kageyama, R. (2001) Hes1 and Hes3 regulate maintenance of the isthmic organizer and development of the mid/hindbrain. EMBO J. 20, 4454–4466.[CrossRef][Medline]
Ishibashi, M., Ang, S.-L., Shiota, K., Nakanishi, S., Kageyama, R. & Guillemot, F. (1995) Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix–loop–helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev. 9, 3136–3148.
Jacobsen, C.M., Narita, N., Bielinska, M., Syder, A.J., Gordon, J.I. & Wilson, D.B. (2002) Genetic mosaic analysis reveals that GATA-4 is required for proper differentiation of mouse gastric epithelium. Dev. Biol. 241, 34–46.[CrossRef][Medline]
Jenny, M., Uhl, C., Roche, C., Duluc, I., Guillermin, V., Guillemot, F., Jensen, J., Kedinger, M. & Gradwohl, G. (2002) Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J. 21, 6338–6347.[CrossRef][Medline]
Jensen, J. (2004) Gene regulatory factors in pancreatic development. Dev. Dyn. 229, 176–200.[CrossRef][Medline]
Jensen, J., Pedersen, E.E., Galante, P., Hald, J., Heller, R.S., Ishibashi, M., Kageyama, R., Guillemot, F., Serup, P. & Madsen, O.D. (2000) Control of endodermal endocrine development by Hes-1. Nat. Genet. 24, 36–44.[CrossRef][Medline]
Jonsson, J., Carlsson, L., Edlund, T. & Edlund, H. (1994) Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371, 606–609.[CrossRef][Medline]
Kageyama, R., Ohtsuka, T. & Kobayashi, T. (2007) The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development 134, 1243–1251.
Kageyama, R., Ohtsuka, T., Hatakeyama, J. & Ohsawa, R. (2005) Roles of bHLH genes in neural stem cell differentiation. Exp. Cell Res. 306, 343–348.[CrossRef][Medline]
Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., Macdonald, R.J. & Wright, C.V.E. (2002) The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat. Genet. 32, 128–134.[CrossRef][Medline]
Krapp, A., Knöfler, M., Ledermann, B., Bürki, K., Berney, C., Zoerkler, N., Hagenbüchle, O. & Wellauer, P.K. (1998) The bHLH protain PTF-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev. 12, 3752–3763.
Lee, C.S., Perreault, N., Brestelli, J.E. & Kaestner, K.H. (2002) Neurogenin3 is essential for the proper specification of gastric enteroendocrine cells and the maintenance of gastric epithelial cell identity. Genes Dev. 16, 1488–1497.
Lee, J.C., Smith, S.B., Watada, H., Lin, J., Scheel, D., Wang, J., Mirmira, R.G. & German, M.S. (2001) Regulation of the pancreatic pro-endocrine gene neurogenin3. Diabetes 50, 928–936.[CrossRef][Medline]
Offield, M.F., Jetton, T.L., Labosky, P.A., Ray, M., Stein, R.W., Magnuson, M.A., Hogan, B.L. & Wright, C.V. (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122, 983–995.[Abstract]
Ohsawa, R., Ohtsuka, T. & Kageyama, R. (2005) Mash1 and Math3 are required for development of branchiomotor neurons and maintenance of neural progenitors. J. Neurosci. 25, 5857–5865.
Radtke, F. & Clevers, H. (2005) Self-renewal and cancer of the gut: two sides of a coin. Science 307, 1904–1909.
Sasai, Y., Kageyama, R., Tagawa, Y., Shigemoto, R. & Nakanishi, S. (1992) Two mammalian helix–loop–helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev. 6, 2620–2634.
Schonhoff, S.E., Giel-Moloney, M. & Leiter, A.B. (2004) Neurogenin 3-expressing progenitor cells in the gastrointestinal tract differentiate into both endocrine and non-endocrine cell types. Dev. Biol. 270, 443–454.[CrossRef][Medline]
Schubert, M.L. (2002) Gastric secretion. Curr. Opin. Gastroenterol. 18, 639–649.[CrossRef][Medline]
Schwitzgebel, V.M., Scheel, D.W., Conners, J.R., Kalamaras, J., Lee, J.E., Anderson, D.J., Sussel, L., Johnson, J.D. & German, M.S. (2000) Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 127, 3533–3542.[Abstract]
Sosa-Pineda, B., Chowdhury, K., Torres, M., Oliver, G. & Gruss, P. (1997) The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. Nature 386, 399–402.[CrossRef][Medline]
Sumazaki, R., Shiojiri, N., Isoyama, S., Masu, M., Keino-Masu, K., Osawa, M., Nakauchi, H., Kageyama, R. & Matsui, A. (2004) Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nat. Genet. 36, 83–87.[CrossRef][Medline]
van Es, J.H., van Gijn, M.E., Riccio, O., van den Born, M., Vooijs, M., Begthel, H., Cozijnsen, M., Robine, S., Winton, D.J., Radtke, F. & Clevers, H. (2005) Notch/
-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963.[CrossRef][Medline]
Yang, Q., bermingham, N.A., Finegold, M.J. & Zoghbi, H.Y. (2001) Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294, 2155–2158.
Received: 14 July 2007
Accepted: 11 October 2007
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