Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm

Jianwene Que, Tadashi Okubo, James R. Goldenring, Ki Taek Nam, Reiko Kurotani, Edward E. Morrisey, Olena Taranova, Larysa H. Pevny, Brigid L.M. Hogan

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313 Citations (Scopus)

Abstract

Sox2 is expressed in developing foregut endoderm, with highest levels in the future esophagus and anterior stomach. By contrast, Nkx2.1 (Titf1) is expressed ventrally, in the future trachea. In humans, heterozygosity for SOX2 is associated with anopthalmia-esophageal-genital syndrome (OMIM 600992), a condition including esophageal atresia (EA) and tracheoesophageal fistula (TEF), in which the trachea and esophagus fail to separate. Mouse embryos heterozygous for the null allele, Sox2EGFP, appear normal. However, further reductions in Sox2, using Sox2LP and Sox2COND hypomorphic alleles, result in multiple abnormalities. Approximately 60% of Sox2EGFPICOND embryos have EA with distal TEF in which Sox2 is undetectable by immunohistochemistry or western blot. The mutant esophagus morphologically resembles the trachea, with ectopic expression of Nkx2.1, a columnar, diliated epithelium, and very few p63+ basal cells. By contrast, the abnormal foregut of Nkx2.1-null embryos expresses elevated Sox2 and p63, suggesting reciprocal regulation of Sox2 and Nkx2.1 during early dorsaltventral foregut patterning. Organ culture experiments further suggestthat FGF signaling from the ventral mesenchyme regulates Sox2 expression in the endoderm. In the 40% Sox2EGFPICOND embryos in which Sox2 levels are -18% of wild type there is no TEF. However, the esophagus is still abnormal, with luminal mucus-producing cells, fewer p63+ cells, and ectopic expression of genes normally expressed in glandular stomach and intestine. In all hypomorphic embryos the forestomach has an abnormal phenotype, with reduced keratinization, ectopic mucus cells and columnar epithelium. These findings suggest that Sox2 plays a second role in establishing the boundary between the keratinized, squamous esophagus/ forestomach and glandular hindstomach.

Original languageEnglish
Pages (from-to)2521-2531
Number of pages11
JournalDevelopment
Volume134
Issue number13
DOIs
Publication statusPublished - 2007 Jul

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology

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    Que, J., Okubo, T., Goldenring, J. R., Nam, K. T., Kurotani, R., Morrisey, E. E., Taranova, O., Pevny, L. H., & Hogan, B. L. M. (2007). Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development, 134(13), 2521-2531. https://doi.org/10.1242/dev.003855