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First published online December 7, 2008
doi: 10.1242/10.1242/dev.023564

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Lessons from a gene regulatory network: echinoderm skeletogenesis provides insights into evolution, plasticity and morphogenesis

Department of Biological Sciences, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, PA 15213, USA.

View larger version (8K): [in this window] [in a new window]   Fig. 1. Territories of the late-blastula stage sea urchin embryo. The different cell territories of the embryo are shown in different colors, and the central blastocoel cavity is shaded gray. The oral-aboral (OA) and animal-vegetal (AV) axes are also shown. AE, aboral ectoderm; AP, apical plate; BC, presumptive blastocoelar cells; EN, endoderm; NSM, non-skeletogenic mesoderm; OE, oral ectoderm; OLE, oral-lateral ectoderm; PC, presumptive pigment cells; PMC, primary mesenchyme cells (skeletogenic mesoderm); SMic, small micromeres.

View larger version (98K): [in this window] [in a new window]   Fig. 2. Development of the embryonic skeleton of euechinoid sea urchins. (A) A living sea urchin embryo (Lytechinus variegatus) at the late gastrula stage. The PMCs adopt a characteristic ring-like pattern within the blastocoel and secrete two skeletal rudiments (arrowheads). (B) A living pluteus larva (L. variegatus) viewed with partially crossed polarizers (image courtesy of Dr Rachel Fink, Mount Holyoke College). The mineralized skeleton (arrowhead) is birefringent. (C) Scanning electron micrograph of the late embryonic skeleton (Dendraster excentricus), with all cellular material removed.

View larger version (7K): [in this window] [in a new window]   Fig. 3. Main layers of regulatory control within the PMC GRN. The earliest inputs into the PMC GRN are from maternal factors (blue box), followed by those of early specification genes (yellow box), and late transcriptional regulators (red box). As a consequence of these regulatory functions, two classes of terminal differentiation genes (green boxes) are activated: one that controls morphogenetic behaviors of the PMCs (morphoregulatory genes) and one that governs the synthesis of the endoskeleton (biomineralization genes). Regulatory interactions within and between levels are indicated by arrows.

View larger version (7K): [in this window] [in a new window]   Fig. 4. Activation of the PMC GRN. Selected components of the maternal (blue) and early specification regulatory layers (yellow) are shown (see also Fig. 3). β-Catenin is stabilized in micromeres and in other vegetal blastomeres by a maternally controlled vegetal stabilization system (MVS), which requires the function of Dishevelled and other maternal Wnt signaling components. β-Catenin, acting with TCF, directly activates (green arrow) pmar1 in the micromeres. Throughout most of the embryo, HesC represses (blue line) early PMC specification genes. This repression is relieved in the micromere territory, where Pmar1 blocks hesC expression (red line), either directly or indirectly. Note that additional mechanisms play a role in restricting pmar1 expression to the micromeres, as β-catenin is stabilized throughout a broader vegetal domain. Similarly, although hesC is repressed throughout the micromere territory, unknown mechanisms restrict the activation of downstream PMC specification genes to the large micromere lineage.

View larger version (10K): [in this window] [in a new window]   Fig. 5. Selected regulatory interactions among early specification genes and late transcriptional regulators in the micromere-PMC GRN. This schematic is based on the work of Oliveri et al. (Oliveri et al., 2008), although certain gene interactions have been omitted from their GRN, either for clarity or because the data supporting the links are equivocal. Yellow boxes indicate early specification genes and red boxes indicate late transcriptional regulators. Two of the early specification genes shown (ets1 and tbr) are also expressed maternally (indicated by stippling). The interactions shown are based on morpholino knockdown studies and may be indirect. Arrows indicate positive interactions and bars indicate negative interactions.

View larger version (32K): [in this window] [in a new window]   Fig. 6. Evolutionary modifications in echinoderm skeletogenesis. Only embryonic and larval stages are illustrated. Green cells indicate non-skeletogenic mesoderm, red cells indicate skeletogenic mesoderm, and heavy black lines represent skeletal rods. (A) The ancestral echinoderm exhibited indirect development and had an adult skeleton. The embryo had an ancestral program of mesoderm specification but lacked a skeleton. (B) In the ancestral echinoid, the adult program of biomineralization was imported into the late embryo. This pattern of skeletogenesis is still seen in modern cidaroid sea urchins. (C) In modern euechinoids, a second heterochronic change occurred, shifting the skeletogenic program into the early embryo. This change was associated with the invention of micromeres and an early-ingressing, skeletogenic mesenchyme (PMCs). It required the establishment of new regulatory links between the ancestral skeletogenic GRN and an even more ancient system of early patterning mediated by β-catenin. It was also associated with the invention of a PMC-derived signal that suppresses the skeletogenic potential of NSM cells (white arrows).

View larger version (24K): [in this window] [in a new window]   Fig. 7. Alternative deployment of the micromere-PMC GRN. (A) In undisturbed embryos, only micromeres (red cells in the early embryo), or more precisely, their large daughter cells, give rise to PMCs (red cells at the blastula stage) and the embryonic skeleton (red rods in the early larva). (B,C) Removal of micromeres or PMCs leads to deployment of the skeletogenic GRN by NSM cells, which are derived from macromeres (yellow) (Hörstadius, 1939; Ettensohn, 1992). (D-F) Animal cells, derived from mesomeres (blue), can be induced to activate the skeletogenic GRN by LiCl treatment (Livingston and Wilt, 1989), by the mis-expression of Delta (Sweet et al., 2002) or of Pmar1 (Oliveri et al., 2002), or by inductive signals from micromeres (Minokawa et al., 1997).

View larger version (56K): [in this window] [in a new window]   Fig. 8. Alternative deployment of the micromere-PMC GRN by NSM cells. (A) An expanded view of the PMC GRN [modified, with permission, from Oliveri et al. (Oliveri et al., 2008)]. Many regulatory components of the micromere-PMC GRN are normally deployed in NSM cells (black ovals). One key regulator not expressed by these cells is alx1 (dark blue box). alx1 controls a subcircuit that activates biomineralization and morphoregulatory genes via intermediaries such as dri, foxB (light blue boxes) and snail (not shown). (B-D) Ectopic deployment of alx1 during NSM transfating (L. variegatus). (B) An embryo at the mesenchyme blastula stage. alx1 mRNA expression (dark purple) is restricted to PMCs. (C) A mesenchyme blastula stage embryo immediately after the microsurgical removal of PMCs. (D) An embryo 6 hours after the microsurgical removal of PMCs. alx1 is expressed ectopically (dark purple) by NSM cells at the tip of the archenteron. Activation of alx1 in NSM cells occurs by a novel, pmar1-independent mechanism. (E) Expression of alx1 is sufficient to trigger NSM transfating. Co-injection of alx1 mRNA and a lineage tracer (green nuclear label) into one macromere at the 16-cell stage induces descendants of the labeled cell to adopt the PMC fate, as shown by immunostaining using a monoclonal antibody that recognizes MSP130 proteins, a family of PMC-specific cell surface proteins (red). White arrows mark transfated cells. Figure modified, with permission, from Ettensohn et al. (Ettensohn et al., 2007).

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