Transcriptional Dynamics of Endodermal Organ Formation

Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Developmental Dynamics (Impact Factor: 2.38). 01/2009; 238(1):29-42. DOI: 10.1002/dvdy.21810
Source: PubMed


Although endodermal organs including the liver, pancreas, and intestine are of significant therapeutic interest, the mechanism by which the endoderm is divided into organ domains during embryogenesis is not well understood. To better understand this process, global gene expression profiling was performed on early endodermal organ domains. This global analysis was followed up by dynamic immunofluorescence analysis of key transcription factors, uncovering novel expression patterns as well as cell surface proteins that allow prospective isolation of specific endodermal organ domains. Additionally, a repressive interaction between Cdx2 and Sox2 was found to occur at the prospective stomach-intestine border, with the hepatic and pancreatic domains forming at this boundary, and Hlxb9 was revealed to have graded expression along the dorsal-ventral axis. These results contribute to understanding the mechanism of endodermal organogenesis and should assist efforts to replicate this process using pluripotent stem cells.

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    • "specified along the anterior–posterior axis of the DE-derived primitive gut tube [9] [10]. Liver and ventral pancreas arise from the anterior portion of the foregut endoderm while the dorsal pancreas and duodenum originate from the posterior domain of foregut anterior endoderm [11]. The posterior portion of the gut endoderm develops into mid-and hindgut endoderm that later give rise to the small and large intestine [12]. "
    Dataset: Study II

    Full-text · Dataset · Nov 2015
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    • "In the mouse, Mnx1 is expressed in the motor neurons, notochord, the entire dorsal endoderm and the ventral prepancreatic endoderm at the embryonic day 8 (E8) (Tanabe et al., 1998; Li et al., 1999). Endodermal Mnx1 expression is transient and forms a dorsal-ventral gradient at E9.5 (Sherwood et al., 2009), with expression persisting in both pancreatic buds at E10.5, and being downregulated between E10.5 (Li et al., 1999) and E12.5 (Harrison et al., 1999). In the adult mouse pancreas, Mnx1 is specifically expressed in mature β-cells (Harrison et al., 1999; Li et al., 1999). "
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    ABSTRACT: Homozygous Mnx1 mutation causes permanent neonatal diabetes in humans, but via unknown mechanisms. Our systematic and longitudinal analysis of Mnx1 function during murine pancreas organogenesis and into the adult uncovered novel stage-specific roles for Mnx1 in endocrine lineage allocation and β-cell fate maintenance. Inactivation in the endocrine-progenitor stage shows that Mnx1 promotes β-cell while suppressing δ-cell differentiation programs, and is crucial for postnatal β-cell fate maintenance. Inactivating Mnx1 in embryonic β-cells (Mnx1Δbeta) caused β-to-δ-like cell transdifferentiation, which was delayed until postnatal stages. In the latter context, β-cells escaping Mnx1 inactivation unexpectedly upregulated Mnx1 expression and underwent an age-independent persistent proliferation. Escaper β-cells restored, but then eventually surpassed, the normal pancreatic β-cell mass, leading to islet hyperplasia in aged mice. In vitro analysis of islets isolated from Mnx1Δbeta mice showed higher insulin secretory activity and greater insulin mRNA content than in wild-type islets. Mnx1Δbeta mice also showed a much faster return to euglycemia after β-cell ablation, suggesting that the new β-cells derived from the escaper population are functional. Our findings identify Mnx1 as an important factor in β-cell differentiation and proliferation, with the potential for targeting to increase the number of endogenous β-cells for diabetes therapy.
    Full-text · Article · Nov 2015 · Development
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    • "domain, from which the stomach develops (McCracken et al., 2014; Sherwood et al., 2009), formed a boundary with both the Pdx1 + and Sox9 + domains (Figures 2A–2A 00 ). Very few cells co-expressing Sox2, Pdx1, and Sox9 were observed at this boundary (Figures 2A–2A 00 ). "
    Dataset: mmc9

    Full-text · Dataset · Oct 2015
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