PRb-mediated Control of Epithelial Cell Proliferation and Indian Hedgehog Expression in Mouse Intestinal Development

Overview

Journal BMC Dev Biol

Publisher Biomed Central

Specialties Biology
Reproductive Medicine

Date 2007 Jan 30

PMID 17257418

Citations 14

Authors

Hai-Su Yang

Philip W Hinds

Affiliations

Soon will be listed here.

Abstract

Background: Self-renewal of the epithelium of the small intestine is a highly regulated process involving cell proliferation and differentiation of stem cells or progenitor cells located at the bottom of the crypt, ending ultimately with extrusion of the terminally differentiated cells at the tip of villus.

Results: Here, we utilized the Cre/loxP system to investigate the function of the retinoblastoma protein, pRb in intestinal epithelium. pRb null mice displayed a profoundly altered development of the intestine with increased proliferation and abnormal expression of differentiation markers. Loss of pRb induces cell hyperproliferation in the proliferative region (crypt) as well as in the differentiated zone (villi). The absence of pRb further results in an increase in the population of enterocytes, goblet, enteroendocrine and Paneth cells. In addition, differentiated enteroendocrine cells failed to exit the cell cycle in the absence of pRb. These proliferative changes were accompanied by increased expression of Indian hedgehog and activation of hedgehog signals, a known pathway for intestinal epithelial cell proliferation.

Conclusion: Our studies have revealed a unique function of pRb in intestine development which is critical for controlling not only the proliferation of a stem cell or progenitor cell population but that of terminally differentiated cells as well.

Citing Articles

Osteosarcoma: prognosis plateau warrants retinoblastoma pathway targeted therapy.

Ballatori S, Hinds P Signal Transduct Target Ther. 2017; 1:16001.

PMID: 29263893 PMC: 5657420. DOI: 10.1038/sigtrans.2016.1.

Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer.

Parisi T, Bronson R, Lees J Oncogene. 2015; 34(48):5890-9.

PMID: 25745996 PMC: 4668801. DOI: 10.1038/onc.2015.30.

IGF-2 is necessary for retinoblastoma-mediated enhanced adaptation after small-bowel resection.

Choi P, Sun R, Sommovilla J, Diaz-Miron J, Guo J, Erwin C J Gastrointest Surg. 2014; 18(11):1887-93.

PMID: 25002022 PMC: 4201888. DOI: 10.1007/s11605-014-2586-1.

Viral oncogene expression in the stem/progenitor cell compartment of the mouse intestine induces adenomatous polyps.

Saenz Robles M, Chong J, Koivisto C, Trimboli A, Liu H, Leone G Mol Cancer Res. 2014; 12(10):1355-64.

PMID: 24994749 PMC: 4201981. DOI: 10.1158/1541-7786.MCR-14-0166.

The retinoblastoma tumor suppressor and stem cell biology.

Sage J Genes Dev. 2012; 26(13):1409-20.

PMID: 22751497 PMC: 3403009. DOI: 10.1101/gad.193730.112.

References

Darmoul D, Brown D, Selsted M, Ouellette A . Cryptdin gene expression in developing mouse small intestine. Am J Physiol. 1997; 272(1 Pt 1):G197-206. DOI: 10.1152/ajpgi.1997.272.1.G197. View

Ciarmatori S, Scott P, Sutcliffe J, McLees A, Alzuherri H, Dannenberg J . Overlapping functions of the pRb family in the regulation of rRNA synthesis. Mol Cell Biol. 2001; 21(17):5806-14. PMC: 87300. DOI: 10.1128/MCB.21.17.5806-5814.2001. View

Kucherlapati M, Nguyen A, Bronson R, Kucherlapati R . Inactivation of conditional Rb by Villin-Cre leads to aggressive tumors outside the gastrointestinal tract. Cancer Res. 2006; 66(7):3576-83. DOI: 10.1158/0008-5472.CAN-05-2699. View

Kim S, Roth K, Coopersmith C, Pipas J, Gordon J . Expression of wild-type and mutant simian virus 40 large tumor antigens in villus-associated enterocytes of transgenic mice. Proc Natl Acad Sci U S A. 1994; 91(15):6914-8. PMC: 44308. DOI: 10.1073/pnas.91.15.6914. View

Potten C, Loeffler M . Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development. 1990; 110(4):1001-20. DOI: 10.1242/dev.110.4.1001. View

Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K, Debril M . The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation. Dev Cell. 2002; 3(6):903-10. DOI: 10.1016/s1534-5807(02)00360-x. View

Ramalho-Santos M, Melton D, McMahon A . Hedgehog signals regulate multiple aspects of gastrointestinal development. Development. 2000; 127(12):2763-72. DOI: 10.1242/dev.127.12.2763. View

Hurford Jr R, Cobrinik D, Lee M, Dyson N . pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Genes Dev. 1997; 11(11):1447-63. DOI: 10.1101/gad.11.11.1447. View

Madison B, Dunbar L, Qiao X, Braunstein K, Braunstein E, Gumucio D . Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J Biol Chem. 2002; 277(36):33275-83. DOI: 10.1074/jbc.M204935200. View

10.

CHANDRASEKARAN C, Coopersmith C, Gordon J . Use of normal and transgenic mice to examine the relationship between terminal differentiation of intestinal epithelial cells and accumulation of their cell cycle regulators. J Biol Chem. 1996; 271(45):28414-21. DOI: 10.1074/jbc.271.45.28414. View

11.

Stappenbeck T, Gordon J . Rac1 mutations produce aberrant epithelial differentiation in the developing and adult mouse small intestine. Development. 2000; 127(12):2629-42. DOI: 10.1242/dev.127.12.2629. View

12.

Classon M, Dyson N . p107 and p130: versatile proteins with interesting pockets. Exp Cell Res. 2001; 264(1):135-47. DOI: 10.1006/excr.2000.5135. View

13.

Lee M, Williams B, Mulligan G, Mukai S, Bronson R, Dyson N . Targeted disruption of p107: functional overlap between p107 and Rb. Genes Dev. 1996; 10(13):1621-32. DOI: 10.1101/gad.10.13.1621. View

14.

Sherr C . Cancer cell cycles. Science. 1996; 274(5293):1672-7. DOI: 10.1126/science.274.5293.1672. View

15.

Lee E, Chang C, Hu N, Wang Y, Lai C, Herrup K . Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature. 1992; 359(6393):288-94. DOI: 10.1038/359288a0. View

16.

Jacks T, Fazeli A, Schmitt E, Bronson R, Goodell M, Weinberg R . Effects of an Rb mutation in the mouse. Nature. 1992; 359(6393):295-300. DOI: 10.1038/359295a0. View

17.

Lipinski M, Jacks T . The retinoblastoma gene family in differentiation and development. Oncogene. 2000; 18(55):7873-82. DOI: 10.1038/sj.onc.1203244. View

18.

Stappenbeck T, Wong M, Saam J, Mysorekar I, Gordon J . Notes from some crypt watchers: regulation of renewal in the mouse intestinal epithelium. Curr Opin Cell Biol. 1999; 10(6):702-9. DOI: 10.1016/s0955-0674(98)80110-5. View

19.

Dannenberg J, VAN ROSSUM A, Schuijff L, Te Riele H . Ablation of the retinoblastoma gene family deregulates G(1) control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev. 2000; 14(23):3051-64. PMC: 317114. DOI: 10.1101/gad.847700. View

20.

Weinberg R . The retinoblastoma protein and cell cycle control. Cell. 1995; 81(3):323-30. DOI: 10.1016/0092-8674(95)90385-2. View