Skip to main content
SpringerLink
Log in

Lack of reelin modifies the gene expression in the small intestine of mice

  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

We recently demonstrated that the mucosa of the small intestine of the rat expresses reelin and some components of its signaling system. The current study evaluates whether reelin affects the intestinal gene expression profile using microarray analysis and reeler mice, a natural mutant in which reelin is not expressed. The effect of the mutation on body weight and intestinal morphology is also evaluated. The mutation reduces body and intestinal weight during the first 2 months of age and modifies the morphology of the crypts and villi. For the microarray assays, total RNA was obtained from either isolated epithelial cells or intact small intestine. Of the 45,101 genes present in the microarray the mutation significantly alters the expression of 62 genes in the isolated epithelial cell samples and of 84 in the intact small intestine. The expression of 83% of the genes tested for validation was substantiated by reverse transcriptase polymerase chain reaction. The mutation notably up-regulates genes involved in intestinal metabolism, while it down-regulates genes related with immune response, inflammation, and tumor development. Genes involved in cell proliferation, differentiation, apoptosis, membrane transport and cytoskeleton are also differently expressed in the reeler mice as compared with the control. This is the first report showing that the lack of reelin modifies intestinal morphology and gene expression profile and suggests a role for reelin in intestinal epithelium homeostasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

Abca1:

ATP-binding cassette subfamily A member 1

Angptl4:

angiopoietin-like 4

Ap2b1:

adaptor-related protein complex 2 beta 1 subunit

ApoER2:

apolipoprotein E receptor 2

Arrb1:

arrestin, beta 1

Bmp1:

bone morphogenetic protein 1

Ccl3:

chemokine (C–C motif) ligand 3

Cdx2:

caudal-type homeo box 2

Clca2:

chloride channel calcium activated 2

Cxcl10:

chemokine (C-X-C motif) ligand 10

Dmbt1:

deleted in malignant brain tumors 1

Dtx3l:

deltex 3-like

Duoxa2:

dual oxidase maturation factor 2

EphA1:

Eph receptor A1

FDR:

false discovery rate

Foxm1:

forkhead box M1

Frk:

Fyn-related kinase

Herc5:

Hect domain and RLD 5

Isg15:

ISG15 ubiquitin-like modifier

Ostb:

organic solute transporter beta

Pik3ca:

phosphatidylinositol 3-kinase catalytic alpha polypeptide

Ppara:

peroxisome proliferator activated receptor alpha

Pycard:

PYD and CARD domain containing

Scarb2:

scavenger receptor class B, member 2

Tm4sf4:

transmembrane 4 superfamily member 4

Ucp2:

uncoupling protein 2

Usp18:

ubiquitin specific peptidase 18

VldlR:

very low-density lipoprotein receptor.

References

  1. Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, Herfarth HH, Jobin C, Ting JP (2010) The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med 207:1045–1056

    Article  PubMed  CAS  Google Scholar 

  2. Attie AD (2007) ABCA1: at the nexus of cholesterol, HDL and atherosclerosis. Trends Biochem Sci 32:172–179

    Article  PubMed  CAS  Google Scholar 

  3. Ballatori N, Fang F, Christian WV, Li N, Hammond CL (2008) Ostalpha–Ostbeta is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liver. Am J Physiol Gastrointest Liver Physiol 295:179–186

    Article  Google Scholar 

  4. Beffert U, Morfini G, Bock HH, Reyna H, Brady ST, Herz J (2002) Reelin-mediated signalling locally regulates protein kinase B/Akt and glycogen synthase kinase 3beta. J Biol Chem 277:49958–49964

    Article  PubMed  CAS  Google Scholar 

  5. Bryja V, Gradl D, Schambony A, Arenas E, Schulte G (2007) Beta-arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo. Proc Natl Acad Sci USA 104:6690–6695

    Article  PubMed  CAS  Google Scholar 

  6. 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

    Article  PubMed  CAS  Google Scholar 

  7. D’Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T (1995) A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374:719–723

    Article  PubMed  Google Scholar 

  8. D’Arcangelo G, Miao GG, Curran T (1996) Detection of the reelin breakpoint in reeler mice. Brain Res Mol Brain Res 39:234–236

    Article  PubMed  Google Scholar 

  9. Drover VA, Nguyen DV, Bastie CC, Darlington YF, Abumrad NA, Pessin JE, London E, Sahoo D, Phillips MC (2008) CD36 mediates both cellular uptake of very long chain fatty acids and their intestinal absorption in mice. J Biol Chem 283:13108–13115

    Article  PubMed  CAS  Google Scholar 

  10. Emre Y, Nübel T (2010) Uncoupling protein UCP2: when mitochondrial activity meets immunity. FEBS Lett 584:1437–1442

    Article  PubMed  CAS  Google Scholar 

  11. Falconer DS (1951) Two new mutants “trembler” and “reeler” with neurological actions in the house mouse. J Gent 50:192–205

    Article  Google Scholar 

  12. García-Delgado M, García-Miranda P, Peral MJ, Calonge ML, Ilundáin AA (2007) Ontogeny up-regulates renal Na(+)/Cl(−)/creatine transporter in rat. Biochim Biophys Acta 1768:2841–2848

    Article  PubMed  Google Scholar 

  13. García-Miranda P, Peral MJ, Ilundáin AA (2010) Rat small intestine expresses the reelin-Dab1 signalling pathway. Exp Physiol 223:451–459

    Google Scholar 

  14. Gattas MV, Forteza R, Fragoso MA, Fregien N, Salas P, Salathe M, Conner GE (2009) Oxidative epithelial host defense is regulated by infectious and inflammatory stimuli. Free Radic Biol Med 47:1450–1458

    Article  PubMed  CAS  Google Scholar 

  15. Ge G, Greenspan DS (2006) Developmental roles of the BMP1/TLD metalloproteinases. Birth Defects Res C Embryo Today 78:47–68

    Article  PubMed  CAS  Google Scholar 

  16. Green-Johnson JM, Zalcman S, Vriend CY, Nance DM, Greenberg AH (1995) Suppressed T cell and macrophage function in the “reeler” (rl/rl) mutant, a murine strain with elevated cerebellar norepinephrine concentration. Brain Behav Immun 9:47–60

    Article  PubMed  CAS  Google Scholar 

  17. Guo RJ, Funakoshi S, Lee HH, Kong J, Lynch JP (2010) The intestine-specific transcription factor Cdx2 inhibits beta-catenin/TCF transcriptional activity by disrupting the beta-catenin–TCF protein complex. Carcinogenesis 31:159–166

    Article  PubMed  CAS  Google Scholar 

  18. Guo RJ, Suh ER, Lynch JP (2004) The role of Cdx proteins in intestinal development and cancer. Cancer Biol Ther 3:593–601

    Article  PubMed  CAS  Google Scholar 

  19. He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, Tian Q, Zeng X, He X, Wiedemann LM, Mishina Y, Li L (2004) BMP signalling inhibits intestinal stem cell self-renewal through suppression of Wnt–beta-catenin signalling. Nat Genet 36:1117–1121

    Article  PubMed  CAS  Google Scholar 

  20. Kersten S, Lichtenstein L, Steenbergen E, Mudde K, Hendriks HF, Hesselink MK, Schrauwen P, Müller M (2009) Caloric restriction and exercise increase plasma ANGPTL4 levels in humans via elevated free fatty acids. Arterioscler Thromb Vasc Biol 29:969–974

    Article  PubMed  CAS  Google Scholar 

  21. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 103:1489–1498

    Article  PubMed  CAS  Google Scholar 

  22. Laprise P, Chailler P, Houde M, Beaulieu JF, Boucher MJ, Rivard N (2002) Phosphatidylinositol 3-kinase controls human intestinal epithelial cell differentiation by promoting adherens junction assembly and p38 MAPK activation. J Biol Chem 277:8226–8234

    Article  PubMed  CAS  Google Scholar 

  23. Li C, Hung Wong W (2001) Model-based analysis of oligonucleotide arrays: model validation, design issues and standard error application. Genome Biol 2 RESEARCH0032

  24. Lombardero M, Kovacs K, Horvath E, Salazar I (2007) Hormonal and morphological study of the pituitaries in reeler mice. Int J Exp Pathol 88:165–173

    Article  PubMed  CAS  Google Scholar 

  25. Mariadason JM, Nicholas C, L’Italien KE, Zhuang M, Smartt HJ, Heerdt BG, Yang W, Corner GA, Wilson AJ, Klampfer L, Arango D, Augenlicht LH (2005) Gene expression profiling of intestinal epithelial cell maturation along the crypt–villus axis. Gastroenterology 128:1081–1108

    Article  PubMed  CAS  Google Scholar 

  26. Massalini S, Pellegatta S, Pisati F, Finocchiaro G, Farace MG, Ciafrè SA (2009) Reelin affects chain-migration and differentiation of neural precursor cells. Mol Cell Neurosci 42:341–349

    Article  PubMed  CAS  Google Scholar 

  27. Masumoto J, Taniguchi S, Nakayama J, Shiohara M, Hidaka E, Katsuyama T, Murase S, Sagara J (2001) Expression of apoptosis-associated speck-like protein containing a caspase recruitment domain, a pyrin N-terminal homology domain-containing protein, in normal human tissues. J Histochem Cytochem 49:1269–1275

    Article  PubMed  CAS  Google Scholar 

  28. McConnell BB, Vertino PM (2004) TMS1/ASC: the cancer connection. Apoptosis 9:5–18

    Article  PubMed  CAS  Google Scholar 

  29. Mulcahy JV, Riddell DR, Owen JS (2004) Human scavenger receptor class B type II (SR-BII) and cellular cholesterol efflux. Biochem J 377:741–747

    Article  PubMed  CAS  Google Scholar 

  30. Peral MJ, García-Miranda P, Vázquez-Carretero MD, Gutiérrez G, Ilundain AA (2009) Gene expression profile of the small intestine in reeler mice. J Physiol Sci 59:529, Abstract

    Google Scholar 

  31. Pitha-Rowe IF, Pitha PM (2007) Viral defense, carcinogenesis and ISG15: novel roles for an old ISG. Cytokine Growth Factor Rev 18:409–417

    Article  PubMed  CAS  Google Scholar 

  32. Potten CS (1992) The significance of spontaneous and induced apoptosis in the gastrointestinal tract of mice. Cancer Metastasis Rev 1:179–195

    Article  Google Scholar 

  33. Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB (1999) Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol 277:1–9

    Google Scholar 

  34. Qiu J, Liu Z, Da L, Li Y, Xuan H, Lin Q, Li F, Wang Y, Li Z, Zhao M (2007) Overexpression of the gene for transmembrane 4 superfamily member 4 accelerates liver damage in rats treated with CCl4. J Hepatol 46:266–275

    Article  PubMed  CAS  Google Scholar 

  35. Renner M, Bergmann G, Krebs I, End C, Lyer S, Hilberg F, Helmke B, Gassler N, Autschbach F, Bikker F, Strobel-Freidekind O, Gronert-Sum S, Benner A, Blaich S, Wittig R, Hudler M, Ligtenberg AJ, Madsen J, Holmskov U, Annese V, Latiano A, Schirmacher P, Amerongen AV, D’Amato M, Kioschis P, Hafner M, Poustka A, Mollenhauer J (2007) DMBT1 confers mucosal protection in vivo and a deletion variant is associated with Crohn’s disease. Gastroenterology 133:1499–1509

    Article  PubMed  CAS  Google Scholar 

  36. Scott IC, Imamura Y, Pappano WN, Troedel JM, Recklies AD, Roughley PJ, Greenspan DS (2000) Bone morphogenetic protein-1 processes probiglycan. J Biol Chem 275:30504–30511

    Article  PubMed  CAS  Google Scholar 

  37. Sheng H, Shao J, Townsend CM Jr, Evers BM (2003) Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut 52:1472–1478

    Article  PubMed  CAS  Google Scholar 

  38. Van der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 7:241–260

    Article  Google Scholar 

  39. Wang Z, Ahmad A, Li Y, Banerjee S, Kong D, Sarkar FH (2010) Forkhead box M1 transcription factor: a novel target for cancer therapy. Cancer Treat Rev 36:151–156

    Article  PubMed  CAS  Google Scholar 

  40. Yeaman C, Grindstaff KK, Nelson WJ (1999) New perspectives on mechanisms involved in generating epithelial cell polarity. Physiol Rev 79:73–98

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Junta de Andalucía (CTS 5884) and by a fellowship from the Spanish Ministerio de Educación y Ciencia (AP2007-04201) to M.D. Vázquez-Carretero. We thank Dr. E. Soriano from the University of Barcelona for supplying the reeler mice used at the beginning of this study and Dr. O. Pintado from the University of Sevilla for his technical advice.

Author information

Authors and Affiliations

  1. Departamento de Fisiología y Zoología, Facultad de Farmacia, Universidad de Sevilla, c/o Profesor García González, no. 2, 41012, Sevilla, Spain

    P. García-Miranda, M. D. Vázquez-Carretero, M. J. Peral & A. A. Ilundáin

  2. Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain

    G. Gutiérrez

Authors
  1. P. García-Miranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. D. Vázquez-Carretero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Gutiérrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. J. Peral
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. A. Ilundáin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. J. Peral.

Rights and permissions

Reprints and permissions

About this article

Cite this article

García-Miranda, P., Vázquez-Carretero, M.D., Gutiérrez, G. et al. Lack of reelin modifies the gene expression in the small intestine of mice. J Physiol Biochem 68, 205–218 (2012). https://doi.org/10.1007/s13105-011-0132-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-011-0132-0

Keywords

Search

Navigation