Specification Of Ectoderm And Mesendoderm By Mutually Antagonistic Factors

The animal-vegetal axis of the amphibian oocyte forms as a result of the differential deposition of maternal proteins and mRNAs. Embryonic ectoderm is specified in the animal hemisphere, which contains a set of maternally derived factors that differs from the one in the vegetal hemisphere (King et al., 2005). Cell progeny derived from the animal and the vegetal regions of the egg interact via secreted signaling factors to pattern the early embryo and to generate the basic body plan. Molecular mechanisms for ectoderm specification appear to depend on both the inheritance of specific localized cytoplasmic determinants and on cell-cell interactions in the early embryo (Figure 12.1, A through D).

When the ectodermal part of the blastula (animal cap) is excised and cultured in isolation, it develops into atypical epidermis, whereas many secreted polypeptides, known as mesoderm-inducing factors, are capable of respeci-fying this tissue into mesoderm or endoderm (Harland and Gerhart, 1997). These observations suggest that mesoderm and endoderm (mesendoderm) originate from the embryologic default state that corresponds with ectoderm. In agreement with this view, VegT, a T-box transcription factor, was shown to promote mesendoderm formation by activating the transcription of Nodal-related mesoderm-inducing factors of the transforming growth factor beta (TGFp) superfamily (Zhang et al., 1998). Moreover, antisense oligonucleo-tide-mediated knockdown of maternal VegT RNA suppresses mesendoderm development and promotes the expansion of ectodermal fates, including epidermis and neural tissue (Zhang et al., 1998). Thus, in the absence of meso-derm- and endoderm-inducing signals, ectoderm appears to develop as a default germ layer. Alternatively, ectoderm may be specified by a localized cytoplasmic factor, and this ectodermal determinant could be missing or suppressed in mesodermal and endodermal tissues.

Maternal Vegt

FIGURE 12.1 Early ectoderm development in Xenopus embryos. A, During oogenesis, the maternal determinants Ectodermin and VegT are deposited in the animal hemisphere and the vegetal hemisphere, respectively. B, After fertilization, the egg cortex rotates relative to the cytoplasm core in a microtubule-dependent process known as the cortical-cytoplasmic rotation, which specifies future dorsal and ventral regions of the embryo. The side of sperm entry becomes ventral (V), and the opposite side becomes dorsal (D). C, After cortical rotation, b-catenin accumulates on the dorsal side along the animal-vegetal axis. Ectodermin specifies ectoderm by counteracting mesen-doderm induced by VegT. D, All three germ layers are dorsalized by b-catenin signaling during blastula stages. E, Dorsal ectoderm is influenced by b-catenin signaling and becomes predisposed to neural induction. The Spemann organizer forms in the dorsal subequatorial region as a result of the combined action of VegT and b-catenin signaling. F, During the early gastrula stage, ventral ectoderm is specified as epidermis by BMP signaling, whereas dorsal ectoderm is specified as neural tissue as a result of BMP antagonists secreted by the organizer.

FIGURE 12.1 Early ectoderm development in Xenopus embryos. A, During oogenesis, the maternal determinants Ectodermin and VegT are deposited in the animal hemisphere and the vegetal hemisphere, respectively. B, After fertilization, the egg cortex rotates relative to the cytoplasm core in a microtubule-dependent process known as the cortical-cytoplasmic rotation, which specifies future dorsal and ventral regions of the embryo. The side of sperm entry becomes ventral (V), and the opposite side becomes dorsal (D). C, After cortical rotation, b-catenin accumulates on the dorsal side along the animal-vegetal axis. Ectodermin specifies ectoderm by counteracting mesen-doderm induced by VegT. D, All three germ layers are dorsalized by b-catenin signaling during blastula stages. E, Dorsal ectoderm is influenced by b-catenin signaling and becomes predisposed to neural induction. The Spemann organizer forms in the dorsal subequatorial region as a result of the combined action of VegT and b-catenin signaling. F, During the early gastrula stage, ventral ectoderm is specified as epidermis by BMP signaling, whereas dorsal ectoderm is specified as neural tissue as a result of BMP antagonists secreted by the organizer.

Recent studies identified gene products that specify ectoderm by suppressing mesendoderm development. Ectodermin, a RING-type ubiquitin ligase, was isolated as a maternal gene product with ectoderm-specific expression (Dupont et al., 2005). Ectodermin promotes the ubiquitination and degradation of Smad4, a protein that is associated with Smadl and Smad2, which are components of the BMP and Nodal signaling pathways, respectively. Ecto-dermin inhibits mesendoderm gene markers in presumptive ectodermal tissue and expands Sox2, a neuroectodermal marker, presumably by suppressing Nodal and BMP signaling. Supporting this view is the fact that mesendoder-mal markers are expanded into the animal hemisphere at early gastrula stages in embryos that are depleted of Ectodermin with a specific antisense morpho-lino oligonucleotide (MO). In these embryos, epidermis is expanded at the expense of neural tissue, and this is consistent with upregulated BMP signaling, which is essential for epidermal development (Dupont et al., 2005; also described later).

Xenopus ectodermally expressed mesendoderm antagonist (Xema) is another recently described protein that is involved in ectoderm specification (Suri et al., 2005). Xema is a Foxi-class transcription factor, which is first detectable in the ectoderm during the late blastula stages. Xema suppresses mesendodermal gene markers, whereas Xema MOs promote mesendoderm formation in the ectodermal territory. In contrast with Ectodermin, Xema does not influence the conversion of epidermis into neural tissue, thus indicating that ectoderm development is independent from epidermal and neural specification. Because Xema has been proposed to function as a transcription-al activator (Suri et al., 2005), it is expected to induce additional mesendo-derm inhibitors. These studies suggest that ectoderm is specified via the inhibition of mesendodermal fates by Ectodermin, Xema, and yet uncharac-terized mesendoderm inhibitors. Thus, mutually antagonistic processes operate in early vertebrate embryos to specify ectodermal and mesendodermal cell fates (see Figure 12.1, A through D).

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