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WIREs Dev Biol
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The Caenorhabditis elegans intestine

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Abstract The transcriptional regulatory hierarchy that controls development of the Caenorhabditis elegans endoderm begins with the maternally provided SKN‐1 transcription factor, which determines the fate of the EMS blastomere of the four‐cell embryo. EMS divides to produce the posterior E blastomere (the clonal progenitor of the intestine) and the anterior MS blastomere, a major contributor to mesoderm. This segregation of lineage fates is controlled by an intercellular signal from the neighboring P2 blastomere and centers on the HMG protein POP‐1. POP‐1 would normally repress the endoderm program in both E and MS but two consequences of the P2‐to‐EMS signal are that POP‐1 is exported from the E‐cell nucleus and the remaining POP‐1 is converted to an endoderm activator by complexing with SYS‐1, a highly diverged β‐catenin. In the single E cell, a pair of genes encoding small redundant GATA‐type transcription factors, END‐1 and END‐3, are transcribed under the combined control of SKN‐1, the POP‐1/SYS‐1 complex, as well as the redundant pair of MED‐1/2 GATA factors, themselves direct zygotic targets of SKN‐1 in the EMS cell. With the expression of END‐1/END‐3, the endoderm is specified. END‐1 and END‐3 then activate transcription of a further set of GATA‐type transcription factors that drive intestine differentiation and function. One of these factors, ELT‐2, appears predominant; a second factor, ELT‐7, is partially redundant with ELT‐2. The mature intestine expresses several thousand genes, apparently all controlled, at least in part, by cis‐acting GATA‐type motifs. WIREs Dev Biol 2013, 2:347–367. doi: 10.1002/wdev.93 For further resources related to this article, please visit the WIREs website.

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Cell lineage of the Caenorhabditis elegans intestine (see Ref 28 for original data). The entire intestine is a clone of cells derived from the single E blastomere (shown in red near the top of the figure). Divisions are approximately anterior–posterior, except for the division of the Ea and Ep cells, which are approximately transverse. Lineages on the embryo's left side are depicted by solid lines; lineages on the right side are depicted by the dashed lines. The 20 cells of the mature intestine are arranged as a longitudinal series of two‐cell discs, called ‘ints’, which surround the intestine lumen. The exception is int1, the most anterior disc, which contains four cells. Intestinal growth is approximately continuous through the four larval stages (L1–L4) to the adult, leading to an ∼100‐fold increase in mass. The adult worm (depicted with a red intestine at the bottom of the figure) is ∼1.4 mm in length.

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The 5′‐promoter region of the Caenorhabditis elegans end‐1 gene, showing candidate binding sites for the four transcription factors or transcription factor pathways (SKN‐1, MED‐1/2, POP‐1, and END‐3) that control end‐1 in the single E blastomere and that lead to endoderm specification. The full 1720 bp promoter activates reporter gene expression with an intensity of ‘++++’. A ‘minimal promoter’ containing only 215 bp (including the critical POP‐1 sites and both MED‐1/2 sites) activates reporter gene expression with an intensity of ‘+’. The candidate POP‐1 site at −165 bp is necessary both for transcriptional repression in the MS cell and activation in the E cell. The two MED‐1/2 sites are necessary within a truncated promoter but may not be necessary in the context of the full promoter. Deletions that remove the GATA site at −418 bp significantly decrease the intensity of reporter expression, suggesting that this site could be a direct target of END‐3. Based on Figure 4 of Maduro et al.76 and using the same (somewhat relaxed) sequences for the preferred binding motifs: SKN‐1 = RTCAT; POP‐1 = CTTTGWW; GATA = HGATAR; MED‐1/2 = RAGTATAC. (Reprinted with permission from Ref 76. Copyright 2005)

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Summary of the key processes by which the HMG protein POP‐1 controls the endoderm fate in the single E blastomere. In the mother EMS cell and in MS, the sister of E (and indeed in E if it does not receive a signal from the adjacent P2 cell), POP‐1 in conjunction with UNC‐37 and HDA‐1 represses the endoderm specification genes end‐1 and end‐3. When EMS receives the Wnt‐MAPK‐Src signal from P2, two competing processes are initiated that continue into the E cell daughter. In the nucleus of the (signaled) E cell, increasing levels of the β‐catenin WRM‐1 bind to a C‐terminal region of POP‐1 and stimulate the LIT‐1 kinase to phosphorylate POP‐1. This phosphorylation leads to enhanced nuclear export of POP‐1 and to relief of end‐1 and end‐3 repression. In the competing reaction, the β‐catenin SYS‐1 binds to an N‐terminal region of (unphosphorylated) POP‐1 and the complex then participates in the transcriptional activation of end‐1 and end‐3. (Reprinted with permission from Figure 7 of Ref 85. Copyright 2011)

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The transcription factor network controlling Caenorhabditis elegans endoderm specification and differentiation. The left column represents approximate developmental time (minutes at 20°C after first embryonic division). The middle column contains four differential interference contrast images of early embryos (4, 12, ∼25, and ∼100 total cells). In the four‐cell embryo (top), the EMS and P2 cells are labeled; the EMS nucleus is marked with a yellow dot; the internal boundaries of EMS and P2 are represented by the dashed yellow line; the short arrow represents the Wnt‐MAPK‐Src signal that polarizes EMS in order to produce anterior MS and posterior E blastomeres in the next division. The endoderm (E) lineage is marked with yellow dots in later stages; the MS cell in the 1E cell stage embryo is marked with a white dot. The right column represents the transcription factors and transcription factor interactions at each stage of endoderm development (see text for details). Specification of the endoderm corresponds to activation of the end‐1 and end‐3 genes in the 1E cell. When the endoderm has four cells (4E cell stage at the bottom of the figure), ‘differentiation’ genes are beginning to be expressed. Such genes invariably contain critical TGATAA‐like sites in their promoters, the direct target of the GATA‐factor ELT‐2 and, in a fraction of cases, also ELT‐7.

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