Abstract
Congenital gastric-type heteroplasia is common in intestinal duplications and anomalies, which originate from incomplete resorption of the omphalomesenteric duct during development. Two transcription factors determine the proximodistal specification of the gastrointestinal tract, SOX2, expressed exclusively in the proximal part of the primitive gut, and CDX2, expressed solely in the distal part. Aberrant expression of these factors may result in abnormal development and congenital abnormalities. Therefore, we analyzed the expression of SOX2 and CDX2 in a number of pediatric intestinal anomalies. We investigated the expression pattern of SOX2 and CDX2 in three congenital intestinal anomalies in which ectopic gastric tissue may be present, Meckel's diverticulum (N = 8), persistent ductus omphalomesentericus (N = 14), and intestinal duplications (N = 8). CDX2, but not SOX2, was detected in intestinal epithelial cells in tissue lacking gastric heteroplasia. In gastric-type heteroplasia, a reciprocal expression pattern existed between SOX2 and CDX2 in the gastric and intestinal tissues, respectively. Interestingly, patches of CDX2-positive cells were present within the gastric mucosa in a subset of Meckel's diverticula and intestinal duplications, suggesting that it is not the absence of CDX2, but rather the ectopic expression of SOX2 that leads to gastric tissue in the prospective intestinal tissue. This is in concordance with our previous mouse studies. Collectively, our data indicate that a fine balance between SOX2 and CDX2 expression in the gastrointestinal tract is essential for proper development and that ectopic expression of SOX2 may lead to malformations of the gut.
Similar content being viewed by others
References
Brown RL, Azizkhan RG (1999) Gastrointestinal bleeding in infants and children: Meckel's diverticulum and intestinal duplication. Semin Pediatr Surg 8(4):202–209
Wells JM, Melton DA (1999) Vertebrate endoderm development. Annu Rev Cell Dev Biol 15:393–410
Vane DW, West KW, Grosfeld JL (1987) Vitelline duct anomalies. Experience with 217 childhood cases. Arch Surg 122(5):542–547
Sherwood RI, Chen TY, Melton DA (2009) Transcriptional dynamics of endodermal organ formation. Dev Dyn 238(1):29–42
Gontan C, Guttler T, Engelen E, Demmers J, Fornerod M, Grosveld FG, Tibboel D, Gorlich D, Poot RA, Rottier RJ (2009) Exportin 4 mediates a novel nuclear import pathway for Sox family transcription factors. J Cell Biol 185(1):27–34
Engelen E, Akinci U, Bryne JC, Hou J, Gontan C, Moen M, Szumska D, Kockx C, van Ijcken W, Dekkers DH, Demmers J, Rijkers EJ, Bhattacharya S, Philipsen S, Pevny LH, Grosveld FG, Rottier RJ, Lenhard B, Poot RA (2011) Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes. Nat Genet 43(6):607–611
Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17(1):126–140
Favaro R, Valotta M, Ferri AL, Latorre E, Mariani J, Giachino C, Lancini C, Tosetti V, Ottolenghi S, Taylor V, Nicolis SK (2009) Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat Neurosci 12(10):1248–1256
Gontan C, de Munck A, Vermeij M, Grosveld F, Tibboel D, Rottier R (2008) Sox2 is important for two crucial processes in lung development: branching morphogenesis and epithelial cell differentiation. Dev Biol 317(1):296–309
Ishii Y, Rex M, Scotting PJ, Yasugi S (1998) Region-specific expression of chicken Sox2 in the developing gut and lung epithelium: regulation by epithelial–mesenchymal interactions. Dev Dyn 213(4):464–475
Que J, Luo X, Schwartz RJ, Hogan BL (2009) Multiple roles for Sox2 in the developing and adult mouse trachea. Development 136(11):1899–1907
Taranova OV, Magness ST, Fagan BM, Wu Y, Surzenko N, Hutton SR, Pevny LH (2006) SOX2 is a dose-dependent regulator of retinal neural progenitor competence. Genes Dev 20(9):1187–1202
Que J, Okubo T, Goldenring JR, Nam KT, Kurotani R, Morrisey EE, Taranova O, Pevny LH, Hogan BL (2007) Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development 134(13):2521–2531
Williamson KA, Hever AM, Rainger J, Rogers RC, Magee A, Fiedler Z, Keng WT, Sharkey FH, McGill N, Hill CJ, Schneider A, Messina M, Turnpenny PD, Fantes JA, van Heyningen V, FitzPatrick DR (2006) Mutations in SOX2 cause anophthalmia–esophageal–genital (AEG) syndrome. Hum Mol Genet 15(9):1413–1422
Beck F, Erler T, Russell A, James R (1995) Expression of Cdx-2 in the mouse embryo and placenta: possible role in patterning of the extra-embryonic membranes. Dev Dyn 204(3):219–227
James R, Kazenwadel J (1991) Homeobox gene expression in the intestinal epithelium of adult mice. J Biol Chem 266(5):3246–3251
James R, Erler T, Kazenwadel J (1994) Structure of the murine homeobox gene cdx-2. Expression in embryonic and adult intestinal epithelium. J Biol Chem 269(21):15229–15237
Chawengsaksophak K, James R, Hammond VE, Kontgen F, Beck F (1997) Homeosis and intestinal tumours in Cdx2 mutant mice. Nature 386(6620):84–87
Beck F, Chawengsaksophak K, Waring P, Playford RJ, Furness JB (1999) Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice. Proc Natl Acad Sci USA 96(13):7318–7323
Gao N, White P, Kaestner KH (2009) Establishment of intestinal identity and epithelial–mesenchymal signaling by Cdx2. Dev Cell 16(4):588–599
Raghoebir L, Bakker ER, Mills JC, Swagemakers S, Kempen MB, Munck AB, Driegen S, Meijer D, Grosveld F, Tibboel D, Smits R, Rottier RJ (2012) SOX2 redirects the developmental fate of the intestinal epithelium towards a premature gastric phenotype. J Mol Cell Biol 4(6):377–385
Martin E, Vanier M, Tavian M, Guerin E, Domon-Dell C, Duluc I, Gross I, Rowland J, Kim S, Freund JN (2010) CDX2 in congenital gut gastric-type heteroplasia and intestinal-type Meckel diverticula. Pediatrics 126(3):e723–e727
Episkopou V (2005) SOX2 functions in adult neural stem cells. Trends Neurosci 28(5):219–221
Georges A, Coopman S, Rebeuh J, Molitor G, Rebouissoux L, Dabadie A, Kalach N, Lachaux A, Michaud L (2011) Inlet patch: clinical presentation and outcome in children. J Pediatr Gastroenterol Nutr 52(4):419–423
Macha S, Reddy S, Rabah R, Thomas R, Tolia V (2005) Inlet patch: heterotopic gastric mucosa—another contributor to supraesophageal symptoms? J Pediatr 147(3):379–382
Chen X, Qin R, Liu B, Ma Y, Su Y, Yang CS, Glickman JN, Odze RD, Shaheen NJ (2008) Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers. BMC Gastroenterol 8:1
Dvorak K, Goldman A, Kong J, Lynch JP, Hutchinson L, Houghton JM, Chen H, Chen X, Krishnadath KK, Westra WM (2011) Molecular mechanisms of Barrett's esophagus and adenocarcinoma. Ann N Y Acad Sci 1232:381–391
Kong J, Crissey MA, Funakoshi S, Kreindler JL, Lynch JP (2011) Ectopic Cdx2 expression in murine esophagus models an intermediate stage in the emergence of Barrett's esophagus. PLoS One 6(4):e18280
Acknowledgments
This work was supported by an Erasmus MC grant (LR). The authors are indebted to Tom de Vries Lentsch for excellent art work.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
Ron Smits and Robbert J. Rottier contributed equally to this paper.
Rights and permissions
About this article
Cite this article
Raghoebir, L., Biermann, K., Buscop-van Kempen, M. et al. Disturbed balance between SOX2 and CDX2 in human vitelline duct anomalies and intestinal duplications. Virchows Arch 462, 515–522 (2013). https://doi.org/10.1007/s00428-013-1405-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-013-1405-5