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Switching on the Notochord Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Switching on the notochord Vincent T. Cunliffe and Philip W. Ingham1 Developmental Genetics Programme, University of Sheffield, Sheffield S10 2TN, UK The notochord is a defining characteristic of the chor- ductive interactions are nevertheless critical for the es- date embryo. It is a dorsally located rod of tensile meso- tablishment of some cell lineages (Nishida 1997). In dermal tissue that lies immediately beneath the neural these organisms, notochordal fate is induced by vegetal tube. In vertebrates the notochord functions as a skeletal blastomeres in just 10 cells of the 110-cell embryo (Na- element during early embryogenesis and as a source of katani and Nishida 1994). These 10 cells then divide signals that pattern the neural tube and paraxial meso- twice to produce the entire set of 40 cells that comprises derm. Despite the recent identification of mutations af- the larval notochord. Initial expression of the Ciona in- fecting notochord development in zebrafish, the rather testinalis homolog of the vertebrate Brachyury gene, Ci- modest progress in isolating genes expressed in the no- Bra, coincides precisely with the restriction of early blas- tochord during its differentiation has limited our under- tomeres to a notochordal fate (Yasuoh and Satoh 1993). standing of the molecular mechanisms underpinning its Expression of Brachyury is then maintained exclusively structure and function. In a recent study, Takahashi et in the notochord, in contrast to the situation in verte- al. (1999), using embryos of the primitive chordate, the brate embryos, where Brachyury is expressed in both no- ascidian, have redressed the balance, identifying a large tochord and ventral–posterior mesoderm (Fig. 1). More- number of notochord-specific genes by subtractive clon- over, misexpression of ascidian Brachyury in cells of ing. Their approach, although not novel in principle, is non-notochordal lineages is sufficient to impart to them remarkable for its efficacy and promises to set the stage with the morphological characteristics of notochord for significant advances not only in our appreciation of cells without the need for inductive interactions with the formation and function of the notochord but also in vegetal blastomeres (Yasuo and Satoh 1998). Takahashi understanding how this important structure has evolved. et al. (1999) have now extended this observation and demonstrated that misexpression of Brachyury in the en- doderm of ascidian embryos is sufficient to induce fully Notochord specification and the role of Brachyury differentiated ectopic notochord. This contrasts with the in mesodermal patterning induction of ventral–posterior mesoderm observed when Brachyury was misexpressed in Xenopus animal caps In vertebrates, the notochord develops from the axial (Cunliffe and Smith 1992): Only by coexpressing noggin mesoderm of the gastrula via inductive interactions in- with Brachyury could notochord be induced in this tis- volving the transforming growth factor ␤ (TGF␤)-super- sue (Cunliffe and Smith 1994). Significantly, Noggin is family and fibroblast growth factor (FGF)-family signal- known to function by inhibiting bone morphogenetic ing molecules. After neurulation the notochord lies be- protein (BMP) signaling pathways (Zimmerman et al. neath the floor plate of the neural tube, above the 1996); BMP4 can both ventralize dorsal mesoderm and endoderm, and between the paired somites that extend induce epidermal fate in dissociated animal cap cells, the length of the trunk and the tail. Critical to its func- and at high concentrations BMP4 is sufficient to induce tion, the notochord expresses transcription factors en- ventral mesoderm in animal cap tissue (Dale et al. 1992; coded by the Brachyury, HNF-3␤ and floating head genes Jones et al. 1992. Sasai et al. 1995; Schmidt et al. 1995; (Smith et al. 1991; Ruiz i Altaba and Jessell 1992; Talbot Wilson and Hemmati-Brivanlou 1995). Thus, coexpres- et al. 1995), as well as the secreted factor Sonic hedgehog, sion of Noggin with Brachyury in animal caps removes which patterns the somites and the neural tube (for re- the ventralizing constraint of BMP signaling on meso- view, see Ingham 1995). Studies in the mouse, Xenopus, dermal fate induced by Brachyury, yielding notochord and zebrafish have demonstrated that Brachyury is re- and somitic muscle. quired for differentiation of axial midline mesoderm into Although as in vertebrates, BMP signaling is impli- notochord as well as for the formation of posterior me- cated in epidermal induction and the inhibition of neural sodermal tissues (Chesley 1935; Halpern et al. 1993; fate in ascidians, it appears to have no obvious role in the Schulte-Merker et al. 1992; Conlon et al. 1996). dorsoventral patterning of the mesoderm of these ani- Ascidian development is highly autonomous, yet in- mals: Misexpression of BMP4 does not ventralize dorsal mesoderm, and in any case it is not expressed in the appropriate cell lineage (Miya et al. 1997). Similarly, 1Corresponding author. E-MAIL [email protected]; FAX 441142222788. studies of the expression pattern of BMP2/4 in the GENES & DEVELOPMENT 13:1643–1646 © 1999 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/99 $5.00; www.genesdev.org 1643 Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Cunliffe and Ingham Novel genes involved in notochord specification and function A subtractive library comprising 599 cDNA clones was produced, 501 of which were up-regulated in embryos expressing the Ci-fkh/Ci-Bra construct. Of these, 38 ex- hibited a notochord-specific expression pattern by in situ hybridization, representing a frequency of 6% of the clones in the original library. Another 84 (14%) induced cDNA clones exhibited expression in notochord and other discrete locations in the embryo, giving a total fre- quency of 20% notochord-induced cDNAs. However, a further 81 (14%) of the induced clones exhibited specific expression patterns in locations other than the noto- chord, suggesting that signaling by ectopic notochord in- duces gene expression in other tissues. Figure 1. Expression of Brachyury in ascidian and Xenopus Twenty of the 38 notochord-specific genes are sug- embryos. (a) In situ localization of Ci-Bra mRNA in mid-tailbud gested by Takahashi et al. (1999) to encode proteins with embryo of C. intestinalis. Signal is strongest in posterior noto- no sequence similarities in available databases. Given chord cells (1997). Anterior is to the left; dorsal is up.(b) Noto- the number and size of the existing model genome and chord-specific expression of the lacZ transgene under the con- expressed sequence tag (EST) databases, this suggests trol of the 3.5-kb Ci-Bra promoter in the mid-tailbud embryo of that there are likely to be many specialized aspects of C. intestinalis (a,b) Reprinted, with permission, from Corbo et notochord function that remain to be understood. The al. 1997. Anterior is to the left; dorsal is up.(c) In situ localiza- tion of Xbra mRNA in late gastrula stage Xenopus embryo. remaining 18 genes encode products with sequence simi- Posterior view; dorsal is up. The signal is visible in two do- larity to proteins of known function. These include ex- mains: notochord and ventral–posterior mesoderm. tracellular matrix proteins, cell adhesion molecules, and cytoplasmic signaling pathway components. One gene that is expressed relatively late in notochord formation is a member of the ezrin–radixin–moesin (ERM) family cephalochordate Amphioxus indicate a function for this of polypeptides, which tether components of the plasma gene in specification of ectodermal fate but not in dor- membrane to the actin cytoskeleton (Tsukita and Yone- soventral patterning of the mesoderm (Panopoulou et al. mura 1997). Perhaps this ERM protein plays a role in cell 1998). The absence of a ventralizing function of ascidian intercalation, maintaining the integrity of the notochord BMP4 may therefore explain how misexpression of or producing the changes in notochord cell shape that Brachyury in ascidian endoderm leads directly to the for- contribute to tail extension. mation of ectopic notochord. Taken together, the observations of Ci-Bra and Xeno- pus Brachyury (Xbra) function have implications for the Other Brachyury-inducible genes evolution of mesodermal patterning mechanisms. It is possible that the earliest evolutionary role for Brachyury Tada et al. (1998) previously used a subtractive hybrid- in chordate development was to specify notochord, and ization approach to isolate genes that were activated that of BMP signaling may have been to induce epider- when Xbra was misexpressed in Xenopus animal cap tis- mal fate. Subsequently, the function of BMP signaling in sue. Because no notochord is induced in this scenario, evolution may have been modified to influence the regu- the functions of these putative Xbra target genes are un- latory program under control of Brachyury. This would likely to be related to those characterized by Takahashi then have enabled the specification and patterning of et al. (1999). Of 37 cDNA clones from the subtracted several types of mesodermal tissues in the vertebrates in library, 4 were identified as Brachyury inducible. One addition to notochord, including somite, mesenchyme, cDNA clone that was isolated identified a family of ho- and mesothelium, in a BMP concentration-dependent meodomain protein-encoding cDNAs related to the manner. Mix.1 family of genes. This cDNA, Bix1, is expressed in The simple switch effect of Brachyury in ascidians has mesoderm and endoderm at late blastula and gastrula been exploited by Takahashi et al. (1999) to stunning stages but it is excluded from the dorsal marginal zone of effect. A high efficiency electroporation technique was the early gastrula that is fated to form the notochord. used to introduce plasmid DNA encoding Ci-Bra under Misexpression of Bix1 in the dorsal marginal zone pre- the control of the ascidian fork head/HNF-3␤ (Ci-fkh) vented notochord formation, whereas misexpression of promoter.
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