The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins
Abstract
Little is known about genes that govern the development of the definitive endoderm in mammals; this germ layer gives rise to the intestinal epithelium and various other cell types, such as hepatocytes, derived from the gut. The discovery that the rat hepatocyte transcription factor HNF3 is similar to the Drosophila forkhead gene, which plays a critical role in gut development in the fly, led us to isolate genes containing the HNF3/forkhead (HFH) domain that are expressed in mouse endoderm develop ment. We recovered mouse HNF3β from an embryo cDNA library and found that the gene is first expressed in the anterior portion of the primitive streak at the onset of gastrulation, in a region where definitive endoderm first arises. Its expression persists in axial structures derived from the mouse equivalent of Hensen’s node, namely definitive endoderm and notochord, and in the ventral region of the developing neural tube. Expression of the highly related gene, HNF3α, appears to initiate later than HNF3P and is first seen in midline endoderm cells. Expression. subsequently appears in notochord, ventral neural tube, and gut endoderm in patterns similar to HNF3β. Microscale DNA binding assays show that HNF3 proteins are detectable in the midgut at 9.5 days p.c. At later stages HNF3 mRNAs and protein are expressed strongly in endoderm-derived tissues such as the liver. HNF3 is also the only known hepatocyte enriched transcription factor present in a highly de-dif ferentiated liver cell line that retains the capacity to re differentiate to the hepatic phenotype. Taken together, these studies suggest that HNF3α and HNF3β are involved in both the initiation and maintenance of the endodermal lineage. We also discovered a novel HFH containing gene, HFH-ES.1, that is expressed transiently in posterior ectoderm and mesoderm at the primitive streak stage, and later predominantly in the neural tube. HFH-ES.1 is highly similar in structure and expression profile to the Drosophila HFH gene FD4, suggesting that HFH family members have different, evolutionarily conserved roles in development.
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By the 8-12 somite stage, endoderm patterning has initiated.
“By this stage endoderm patterning has initiated [14,35].”
From A systematic screen for genes expressed in definitive endoderm by Serial Analysis of Gene Expression (SAGE) (2007) · cites this paper as [35]
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Tissue-specific deletion of Foxa2 in pancreatic β cells results in hyperinsulinemic hypoglycemiaPreprint
Sund, N. J., Vatamaniuk, M. Z., Casey, M. A., Ang, S., Magnuson, M. A., Stoffers, D. A., Matschinsky, F. M., & Kaestner, K. H. (2001) · Genes & Development · doi:10.1101/gad.901601 · Cited by 187 · see citing works
“During formation of the definite endoderm from which the pancreatic primordium is derived, Foxa2 mRNA is detected first, followed by Foxa1 and finally Foxa3 (Ang et al. 1993; Monaghan et al. 1993; Sasaki and Hogan 1993).”
BackgroundSelf-citationSmall-Molecule-Driven Hepatocyte Differentiation of Human Pluripotent Stem Cells
Siller, R., Greenhough, S., Naumovska, E., & Sullivan, G. J. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.04.001 · Cited by 203 · see citing works
“We monitored developmentally relevant markers of primitive streak (T, MIXL1, GSC, and FOXA2), mesendoderm (T and FOXA2), and definitive endoderm (HHEX, CER1, SOX17, and FOXA2).”
BackgroundFOXA1: a transcription factor with parallel functions in development and cancer
Bernardo, G. M., & Keri, R. A. (2011) · Bioscience Reports · doi:10.1042/bsr20110046 · Cited by 225 · see citing works
Salivary glands: a paradigm for diversity of gland development.
Denny, P., Ball, W. D., & Redman, R. (1997) · Critical Reviews in Oral Biology and Medicine · doi:10.1177/10454411970080010301 · Cited by 198 · see citing works
Yamanaka, Y., Tamplin, O. J., Beckers, A., Gossler, A., & Rossant, J. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.10.016 · Cited by 182 · see citing works
Self-citationNorris, D. P., & Robertson, E. J. (1999) · Genes & Development · doi:10.1101/gad.13.12.1575 · Cited by 196 · see citing works
“The winged helix factor HNF3b is strongly expressed in the anterior streak and then in the node, notochord, and floor plate (Ang et al. 1993; Monaghan et al. 1993; Sasaki and Hogan 1993), where it is required for the formation of these midline organizing structures (Ang and Rossant 1994; Weinstein…”
BackgroundEarly postnatal lethality in Hoxa-5 mutant mice is attributable to respiratory tract defects.
Aubin, J., Lemieux, M., Tremblay, M. J., Bérard, J., & Jeannotte, L. (1997) · Developmental Biology · doi:10.1006/dbio.1997.8746 · Cited by 194 · see citing works
“AID DB 8746 / 6x31$$$303 12-15-97 04:35:04 dbas in endoderm derivatives during embryogenesis (Sasaki and Hogan, 1993; Monaghan et al., 1993; Ang et al., 1993).”
BackgroundInfluential<i>FoxH1</i>(<i>Fast</i>) functions to specify the anterior primitive streak in the mouse
Hoodless, P. A., Pye, M., Chazaud, C., Labbé, E., Attisano, L., Rossant, J., & Wrana, J. L. (2001) · Genes & Development · doi:10.1101/gad.881501 · Cited by 203 · see citing works
“During gastrulation Foxa2 expression is initiated in the epiblast at the anterior end of the primitive streak (Ang et al. 1993; Monaghan et al. 1993; Ruiz i Altaba et al. 1993), and by late streak stages it is expressed in the node, prospective floor plate of the neural tube, and the axial mesendoderm.”
BackgroundInfluentialSelf-citationTranscriptional dynamics of endodermal organ formation
Sherwood, R. I., Chen, T. A., & Melton, D. A. (2009) · Developmental Dynamics · doi:10.1002/dvdy.21810 · Cited by 191 · see citing works
Dynamic epigenomic landscapes during early lineage specification in mouse embryos
Zhang, Y., Xiang, Y., Yin, Q., Du, Z., Xu, P., Wang, Q., Fidalgo, M., Xia, W., Li, Y., Zhao, Z., et al. (2017) · Nature Genetics · doi:10.1038/s41588-017-0003-x · Cited by 210 · see citing works
Lock, L., & Tzanakakis, E. (2009) · Tissue Engineering. Part A · doi:10.1089/ten.tea.2008.0455 · Cited by 191 · see citing works
Volckaert, T., Campbell, A., Dill, E., Li, C.-G., Minoo, P., & Langhe, S. D. (2013) · Development · doi:10.1242/dev.096560 · Cited by 188 · see citing works
“, 1996), and Foxa2, an endoderm marker (Ang et al., 1993), we found that overexpression of Dkk1 prior to lung initiation affects primary lung field specification in a dose-dependent manner (Fig.”
A glimpse into the molecular entrails of endoderm formationPreprint
Stainier, D. Y. R. (2002) · Genes & Development · doi:10.1101/gad.974902 · Cited by 177 · see citing works
“However, FoxA2, which comes on in endodermal precursors at the onset of gastrulation in both mouse and zebrafish, is essential for mouse foregut and midgut but not hindgut development (Ang et al. 1993; Weinstein et al. 1994; Dufort et al. 1998).”
BackgroundThe hepatocyte nuclear factor 3 (HNF3 or FOXA) family in metabolism.
Kaestner, K. (2000) · Trends in endocrinology and metabolism · doi:10.1016/s1043-2760(00)00271-x · Cited by 183 · see citing works
Mechanisms controlling early development of the liver
Duncan, S. A. (2002) · Mechanisms of Development · doi:10.1016/s0925-4773(02)00328-3 · Cited by 169 · see citing works
Lin, W., Metzakopian, E., Mavromatakis, Y. E., Gao, N., Balaskas, N., Sasaki, H., Briscoe, J., Whitsett, J. A., Goulding, M., Kaestner, K. H., et al. (2009) · Developmental Biology · doi:10.1016/j.ydbio.2009.07.006 · Cited by 154 · see citing works
“0) (Ang et al., 1993), making them good candidates to contribute to the specification of mdDA progenitor identity.”
BackgroundSelf-citationRausa, F. M., Samadani, U., Ye, H., Lim, L., Fletcher, C., Jenkins, N. A., Copeland, N. G., & Costa, R. H. (1997) · Developmental Biology · doi:10.1006/dbio.1997.8744 · Cited by 169 · see citing works
Molecular genetics of Axenfeld-Rieger malformations.
Lines, M. A., Kozlowski, K., & Walter, M. A. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.10.1177 · Cited by 178
p53-Mediated Repression of Alpha-Fetoprotein Gene Expression by Specific DNA Binding
Lee, K. C., Crowe, A. J., & Barton, M. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.2.1279 · Cited by 176 · see citing works
“transactivator, hepatic nuclear factor 3a (HNF-3a [2, 45]), and”
BackgroundFoxa2 is required for the differentiation of pancreatic α-cells
Lee, C. S., Sund, N. J., Behr, R., Herrera, P. L., & Kaestner, K. H. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.10.012 · Cited by 199 · see citing works
“In addition to Foxa2, the related winged helix family members Foxa1 and Foxa3 are expressed at the onset of definite endoderm development, with Foxa2 being activated first, followed by Foxa1, and finally Foxa3 (Ang et al., 1993; Monaghan et al., 1993; Sasaki and Hogan, 1993).”
BackgroundBochkis, I. M., Rubins, N. E., White, P., Furth, E. E., Friedman, J. R., & Kaestner, K. H. (2008) · Nature Medicine · doi:10.1038/nm.1853 · Cited by 186 · see citing works
Turner, D. A., Hayward, P. C., Baillie‐Johnson, P., Rué, P., Broome, R., Faunes, F., & Arias, A. M. (2014) · Development · doi:10.1242/dev.112979 · Cited by 158 · see citing works
“Foxb1 is a member of the Fkh family of transcription factors that has been reported to be expressed in the NMp region during elongation (Ang et al., 1993; Zhao et al., 2007), and thus represents a novel marker for the NMp.”
Characterization of the mouse HNF-4 gene and its expression during mouse embryogenesis
Taraviras, S. L., Monaghan, A. P., Schütz, G., & Kelsey, G. (1994) · Mechanisms of Development · doi:10.1016/0925-4773(94)90017-5 · Cited by 166 · see citing works
Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives
Wang, Z., Dollé, P., Cardoso, W. V., & Niederreither, K. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.05.019 · Cited by 156 · see citing works
Molecular Basis of Vertebrate Endoderm Development
Zorn, A. M., & Wells, J. M. (2007) · International review of cytology · doi:10.1016/s0074-7696(06)59002-3 · Cited by 156 · see citing works
Takayama, K., Inamura, M., Kawabata, K., Sugawara, M., Kikuchi, K., Higuchi, M., Nagamoto, Y., Watanabe, H., Tashiro, K., Sakurai, F., et al. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.04.038 · Cited by 156 · see citing works
“In embryogenesis, the expression of FOXA2 and HNF1a is initially detected in DE or hepatoblasts, respectively and the expression levels of both FOXA2 and HNF1a are elevated as the liver develops [14,15].”
BackgroundGenetic determinants and epigenetic effects of pioneer-factor occupancy
Donaghey, J., Thakurela, S., Charlton, J., Chen, J., Smith, Z. D., Gu, H., Pop, R., Clement, K., Stamenova, E. K., Karnik, R., et al. (2018) · Nature Genetics · doi:10.1038/s41588-017-0034-3 · Cited by 169 · see citing works
- Authors
- Ang, S.-L., Wierda, A., Wong, D., Stevens, K. A., Cascio, S., Rossant, J., & Zaret, K. S.
- Affiliations
- Mount Sinai Hospital (CA)
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 1993-12-01
- Volume
- 119
- Issue
- 4
- Pages
- 1301-1315
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2100715279
- Cited by
- 618
- References
- 0
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 12 · 2023: 5 · 2022: 10 · 2021: 13 · 2020: 5 · 2019: 12 · 2018: 10 · 2017: 14 · 2016: 18 · 2015: 16 · 2014: 18 · 2013: 12 · 2012: 22
- FWCI
- 7.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM 36477)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- definitive endoderm, HNF-3, forkhead transcription factor, gastrulation, primitive streak, Hensen's node, notochord, ventral neural tube, gut endoderm, liver development, mouse embryo
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, DNA-Binding Proteins, Electrophoresis, Endoderm, Gastrula, Intestines, Liver, Mammals, Mice, Inbred Strains, Molecular Sequence Data, Morphogenesis, Nervous System, Nuclear Proteins, Transcription Factors, Gene Expression, In Situ Hybridization, Mice, Hepatocyte Nuclear Factor 3-alpha, Hepatocyte Nuclear Factor 3-beta
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