Conservation Of Neural Induction

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Even more fascinating than the identification of three candidate neural-inducing factors in a relatively short period of time is that these three factors may all act by a related mechanism and that this mechanism appears to be at least partially conserved between ver

Animal cap

Vegetal pole

Animal cap

Vegetal pole

Animal Cap Xenopus

Intact

Dissociated

Intact

Dissociated

+BMP 4 & Dissociate

+BMP 4 & Dissociate

Epidermis

Neural tissue

Epidermis

FIGURE 1.21 Dissociation of animal cap cells prior to gastrula-tion causes most of them to differentiate into neurons in culture. Animal caps can be cultured intact (left) or dissociated into single cells by removing the Ca+2 ions from the medium (middle and right). If the intact caps are put into culture, they develop as epidermis (left). If the dissociated animal cap cells are cultured, they develop into neurons (red; middle). This result supports the hypothesis that the neural fate is actively suppressed by cellular associations in the ectoderm. If the cells are dissociated and then BMP is added to the culture dish, the cells do not become neurons, but instead act as if they are not dissociated and develop as epidermis (right).

Epidermis

Neural tissue

Epidermis

FIGURE 1.21 Dissociation of animal cap cells prior to gastrula-tion causes most of them to differentiate into neurons in culture. Animal caps can be cultured intact (left) or dissociated into single cells by removing the Ca+2 ions from the medium (middle and right). If the intact caps are put into culture, they develop as epidermis (left). If the dissociated animal cap cells are cultured, they develop into neurons (red; middle). This result supports the hypothesis that the neural fate is actively suppressed by cellular associations in the ectoderm. If the cells are dissociated and then BMP is added to the culture dish, the cells do not become neurons, but instead act as if they are not dissociated and develop as epidermis (right).

tebrates and invertebrates (Figure 1.22). Analysis of chordin's sequence revealed an interesting homology with a Drosophila gene called short gastrulation or sog. Sog is expressed in the ventral side of the fly embryo, and mutations in this gene in Drosophila result in defective dor sal-ventral patterning of the embryo. In null mutants of sog, the epidermis expands and the neuro-genic region is reduced. And, like chordin, microinjection of sog into the nonneurogenic region of the embryo causes the formation of ectopic neural tissue. Thus, sog seems to be the functional homolog of chordin. At this point the advantages of fly genetics were important. From analysis of other Drosophila mutants, it was possible to show that sog interacts with a gene called decapentaplegic, or dpp, a TGF-like protein related to the vertebrate genes known as bone-morphogenic proteins, BMPs. Dpp and sog directly antagonize one another in Drosophila. Mutations in dpp have the opposite phenotype as sog mutations; in dpp

Drosophila

Frog dpp.

Drosophila dpp.

Neural Sections Drosophila

Ectoderm

Frog

delaminating neuroblasts

FIGURE 1.22 Vertebrates and invertebrates use similar molecules to pattern the dorsal-ventral axis. The Drosophila embryo in cross section resembles an inverted Xenopus embryo. As described in Figure 1.6, the neurogenic region is in the ventral-lateral Drosophila embryo, whereas in the vertebrate embryo, the neural plate arises from the dorsal side. In the Drosophila, a BMP-like molecule, dpp, inhibits neural differentiation in the ectoderm, and in the vertebrate embryo, the related molecules, BMP2 and BMP4, suppress neural development. In Drosophila, sog (short gastrula) promotes neural development by inhibiting the dpp signaling in the ectoderm in this region, while in the Xenopus, a related molecule, chordin (chd), is one of the neural inducers released from the involuting mesodermal cells and in an analogous way inhibits BMP signaling, allowing neural development in these ectodermal cells.

mutants the neurogenic region expands at the expense of the epidermis, and ectopic expression of dpp causes a reduction in neural tissue. These Drosophila studies motivated studies of the distribution of the BMPs at early stages of Xenopus development, and a similar pattern has emerged. BMP4 is expressed throughout most of the gastrula, but at reduced levels in the organizer and neurogenic animal cap. As expected, recombinant BMP4 can suppress neural induction by chordin, the vertebrate homolog of Sog.

The studies of sog/chordin and dpp/BMP4 lead to two conclusions. First, it appears that the dorsalventral axis of the developing embryo uses similar mechanisms in both the fly and the vertebrate. However, as discussed in the previous section, the neural tissue in the vertebrate is derived from the dorsal side of the animal, while the neurogenic region of the fly is on the ventral side (DeRobertis and Sasai, 1996; Holley et al., 1995). The idea that the vertebrate and arthropod body plans were inverted with respect to one another was first proposed by Geoffry Saint-Hillaire from comparative anatomical studies, and this appears to be confirmed by these recent molecular studies (Figure 1.22). Second, the antagonistic mechanism between sog and dpp in the fly also led to the hypothesis that the various neural inducers might work through a common mechanism, the antagonism of BMP4 signaling. The following three key experiments all indicate that this is indeed the case. First, BMP4 will inhibit neural differentiation of animal caps treated with chordin, noggin. or follistatin. Second, BMP4 will also inhibit neural differentiation of dissociated animal cap cells. Third, antisense BMP4 RNA causes neural differentiation of animal caps without addition of any of the neural inducers. The dominantnegative activin receptor induction of neural tissue can also be understood in this context, since the activin receptor is related to the BMP4 receptor, and additional experiments have shown that the expression of the truncated receptor also blocks endogenous BMP4 signaling (Wilson and Hemmati-Brivanlou, 1995).

Do all three of these neural inducers act equiva-lently to inhibit BMP4 signaling? Biochemical studies have demonstrated that chordin blocks BMP4-receptor interactions by directly binding to the BMP4 with high affinity. Noggin also appears to bind BMP4 with an even greater affinity, while follistatin can bind the related molecules BMP7 and activin. Therefore, it is likely that at least these three neural inducers act by blocking the endogenous epider-malizing BMP4, thereby allowing neural differentiation of the neurogenic ectoderm (Piccolo et al., 1996) (Figure 1.23).

The studies described in Xenopus embryos have provided evidence that these factors are capable of inducing neural tissue, but it is more difficult technically to determine whether these factors are required for neural induction in Xenopus. To study the requirement for BMP inhibition in neural induction, several labs have examined animals that have mutations in one or more of the putative neural inducer genes. Zebrafish with mutations in the chordin gene have reductions in both neural tissue and in other dorsal tissues (Schulte-Merkerr et al., 1997). In mice, targeted deletions have been made in the genes for follistatin, noggin, and chordin. Although deletion of any one of these genes has only minor effects on neural induction, elimination of both noggin and chordin has major effects on neural development. Figure 1.24 shows the nearly headless phenotype of these animals. The cerebral hemispheres of the brain are almost completely absent. Nevertheless, some neural tissue forms in these animals. Thus, while antagonism of the BMP signal via secreted BMP

Ectoderm

Chordin Noggin Follistatin

FIGURE 1.23 The current model of neural induction in amphibian embryos. As the involuting mesodermal cells of the IMZ release several molecules that interfere with the BMP signals between ectodermal cells. Ceberus, chordin, noggin, and follistatin all interfere with the activation of the BMP receptor by the BMPs in the ectoderm and thereby block the anti-neuralizing effects of BMP4. In other words, they "induce" this region of the embryo to develop as neural tissue, ultimately generating the brain, spinal cord, and most of the peripheral nervous system.

FIGURE 1.23 The current model of neural induction in amphibian embryos. As the involuting mesodermal cells of the IMZ release several molecules that interfere with the BMP signals between ectodermal cells. Ceberus, chordin, noggin, and follistatin all interfere with the activation of the BMP receptor by the BMPs in the ectoderm and thereby block the anti-neuralizing effects of BMP4. In other words, they "induce" this region of the embryo to develop as neural tissue, ultimately generating the brain, spinal cord, and most of the peripheral nervous system.

antagonists is clearly required for the development of much of the nervous system, other factors are likely involved.

Experiments with chick embryos and ascidians indicate that at least one of these additional factors is likely a member of the fibroblast growth factor (FGF) family of signaling molecules. In the chick embryo, Streit et al. (2000) found that neural induction actually occurs prior to gastrulation. Moreover, blocking FGF signaling with an FGF receptor inhibitor, called SU5402, prevented this early phase of neural induction. Evidence from the ascidian embryo further supports the role of FGF in neural induction. Ascidians are not vertebrates, but before becoming a sessile adult, they have a "tadpole" intermediate form that resembles a simple vertebrate-like larva, with a notochord and dorsal neural tube. In this animal, BMP antagonists like chordin and noggin do not appear to be involved in the induction of the neural tube. Instead FGF is the critical factor, as for the chick. Does FGF act to antagonize the BMP repression of the neural fate in ectoderm, Noggin, and Chordin? All of the ways in which these two different signaling pathways interact with one another are not yet clear. Nevertheless, there is evidence that the downstream pathway components activated by FGF inhibit BMP inhibition by phospho-rylating Smad proteins (see Box). In addition, a

Noggin Chordin

FIGURE 1.24 Loss of noggin and chordin in developing mice causes severe defects in head development. Left, wild-type mouse embryo, middle loss of noggin only. Right, loss of both noggin and chordin. From ref with permission. Note that only mild defects are present in mice deficient in only noggin, but the head is nearly absent when both genes are knocked out. (From Bachiller et al., 2000)

FIGURE 1.24 Loss of noggin and chordin in developing mice causes severe defects in head development. Left, wild-type mouse embryo, middle loss of noggin only. Right, loss of both noggin and chordin. From ref with permission. Note that only mild defects are present in mice deficient in only noggin, but the head is nearly absent when both genes are knocked out. (From Bachiller et al., 2000)

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