View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Magazine R617 another. Cells derived from the Figure 1 Primer transplanted node form an elongated mesodermal structure, reminiscent of the notochord, and also colonize the The node of the neural tube and the somites of the mouse embryo induced embryo. The types of tissue colonized by the graft are consistent Bruce P. Davidson and with the normal fate of the node cells in intact embryos. The notochord Patrick P.L. Tam and floor plate are known to be sources of inductive signals that About 75 years ago, Spemann and specify and pattern the neurons of Mangold discovered a specific the neural tube, the somites and the population of cells in the amphibian gut. So, during normal development, embryo that, when transplanted to the node and its derivatives appear Anterior Posterior another embryo, had the extraordinary first to specify the developmental property of inducing the formation of fates of different embryonic cell an accessory embryo complete with populations, and then to organize the head and tail structures. This seminal different tissues into a body plan. finding introduced the concept of an Current Biology embryonic organizer capable of What else does the node do? assembling the various tissue Mouse embryos that lack the components along the three activity of a forkhead domain gene, The node (or Hensen’s node, labelled by the blue colour marker of Foxa2 gene embryonic body axes, namely, anterior Foxa2, have neither a node nor a activity), is localized in the anterior region (head)–posterior (tail) (A–P), dorso notochord. The neural tube of these (boxed) of the primitive streak, labelled by the (back)–ventral (front) (D–V) and mutant embryos lacks distinct reddish-brown colour marker of T gene left–right (L–R). Cell populations ventral cell types, which is a likely to activity of the late-streak (7.5-day) mouse displaying similar organizing activity gastrula. The orientation of the be a consequence of the loss of the anterior–posterior (A–P) axis of the embryo is have since been found in fish, avian notochord and floor plate. Whether indicated by the curved double-arrow and mammalian embryos at the loss of the node and its following the curvature of the cylindrical gastrulation, when the distinct germ derivatives also affects the D–V embryo. (Figure courtesy of T. Tsang.) layers (ectoderm, mesoderm and patterning of other organs, such as endoderm) that differentiate into the gut, is unknown. A dramatic various tissues are formed. In the consequence of the loss of the node architecture that is a part of the mouse embryo, such organizer activity is the disruption of the laterality global morphological asymmetry. is found in the cells of the node (once (L–R asymmetry) of the body plan, A contentious issue relating to the called Hensen’s node), a region revealed by the expression of nodal function of the node is its role in discernible as a tight knot of cells and Pitx2 gene activity on both sides determining the A–P axis of the located at the anterior of the primitive instead of just the left side of the embryo. Although embryos deficient streak (the site of cellular ingression body and the abnormal position of in Foxa2 activity develop with D–V and new germ layer formation) of the internal organs. Defects in the L–R and L–R axial defects, a neural tube gastrula-stage embryo (Figure 1). axis are also found in embryos that displaying the correct region-specific form an abnormal notochord or lose neural markers is formed. Mutation of Organizing the body plan the notochord due to degeneration or genes that are expressed in the Like the organizer of other surgical ablation. The potential role prechordal mesoderm and notochord vertebrate embryos, the mouse node of the node in the determination of reveal that derivatives of the node can induce the formation of an laterality is highlighted by the have specific roles in the patterning of embryo-like structure when correlation of left–right defects with parts of the brain. Mutant mice with transplanted onto the flank of the impaired motility of the cilia an inactivated Lhx1 gene, which another gastrula-stage mouse located on the ventral cells of the encodes a LIM-homeodomain factor embryo. Most of the tissues in the node in mutant embryos.The ciliary expressed in the node and the midline induced embryo are derived from the activity of the node cells may either mesoderm, develop microcephaly, host embryo, including the neural be directly responsible for the while mice deficient in Gsc ( a paired tube, somites and parts of the gut, asymmetric distribution of factors homeodomain gene) activity in the which are all assembled in the that determine laterality or perhaps prechordal mesoderm lose Nkx2.1 correct spatial relationship to one reflects some intrinsic cytoskeletal activity, which specifies neuronal R618 Current Biology Vol 10 No 17 Table 1 An early gastrula organizer An intriguing outcome of node Genetic activity in the gastrula organizer and axial mesoderm. transplantation is that the neural Genes Gastrula organizer Axial mesoderm tube of the induced axis lacks the EGO Node Prechordal mesoderm Notochord anterior-most structures (the forebrain and midbrain). The node Signalling molecules Shh ●● ●only becomes morphologically Bmp7 ●●recognizable in embryos that are in Nodal ● advanced gastrulation, and by this Wnt11 ● stage it may have lost the activity Antagonist vs Nodal or BMP that enables the induction of anterior Cerl* ●●(head) structures. If this is so, the Nog ●●predecessor of the node in younger Chrd ●●embryos is expected to contain the ● Dte full activity required to induce both Antagonists vs Wnt the head and the trunk. However, Frzb1 ●● the lack of anterior structures may be Dkk1* ● due to the fact that the host tissues do not have the competence to Cilia and cytoskeletal proteins Kif3a, Kif3b (KIF3) ● respond to the organizing activity of Lrd (LRD) ● the transplanted node. Furthermore, the organizer may have been Transcription factors transplanted so close to the domain Foxa2* ●●● ● T ●●of the prospective neural tube that it Lhx1* ●●● ●can only recruit pre-patterned tissues Gsc* ●● to the new axis rather than inducing a whole new neural tube. A compendium of the genetic activity in mesoderm and notochord). Asterisks mark Lineage analysis of the early the organizer (the node and its predecessor the genes that are also expressed in the mouse gastrula has identified a — the early gastrula organizer, EGO) and its anterior endoderm, shown as brown in population of about 40 cells in the mesodermal derivatives in the embryonic Figure 2c, of the gastrulating embryo. midline (axial mesoderm: prechordal posterior region of the embryo whose descendants colonize the typical types in the ventral forebrain. Mouse genes expressed in the node and its node derivatives and the node itself. embryos lacking the activity of two derivatives encode proteins that may Like the node, this cell population antagonists of bone morphogenetic bind to specific ligands of the Wnt and (the early-gastrula organizer, EGO) protein (BMP) signalling (encoded by transforming growth factor β (TGFβ) expresses a comparable repertoire of Nog and Chrd, co-expressed in the signalling pathways (Figure 2), thus organizer markers (Table 1) and can node and the notochord) or a factor blocking signalling to the receptors of induce a secondary body axis when that counteracts Wnt signalling these pathways. The genes encoding transplanted. However, the (encoded by Dkk1, expressed in the the ligands are expressed in tissues secondary axis remains incomplete, prechordal mesoderm) also do not mostly outside the node in lacking the anterior-most neural develop a normal forebrain. extraembryonic tissues, the peripheral structures of the fore- and midbrain (proximal) ectoderm and the primitive regions, suggesting that independent How does the node work? streak (Figure 2). The expression of head organizing activity is not an The node and its derivatives these Wnt and BMP antagonists may intrinsic property of the EGO. It is express an array of genes encoding create tissue domains in the vicinity of interesting that in the chick, the cell several transcription factors and the node and its derivatives with population in a stage 2–3 embryo, cytoskeletal proteins, as well as the finely modulated signalling activity. equivalent to the EGO, and the signalling ligands and their antagonists Cells surrounding these antagonist Hensen’s node of a stage 4+ embryo, (Table 1). Although mutations in sources are likely to be subjected to which has formed the head process several genes result in gastrulation different signalling activity thereby like the late-streak stage mouse defects that are probably a following distinct developmental embryo, lack the ability to induce consequence of a lack of organizer fates. The node and its derivatives forebrain. The avian organizer only activity, the precise role of these therefore mainly act as the modulator acquires the full axis induction molecules in the signalling processes of the signalling activity of potency at stage 3+/4 (equivalent to remains unknown. Interestingly, some morphogenetic molecules. the mid-streak stage in the mouse) Magazine R619 Figure 2 induction suggests that these anterior tissues do not act like the classical (a) (b) organizer. However, when the EGO is grafted together with the anterior endoderm and epiblast of the early Proximal gastrula, a secondary axis with more Anterior Posterior anterior features is formed. This Distal indicates that the organizing activity of the mouse embryo requires a synergistic interaction between the organizer and germ layer tissues in (c) Bmp4 other embryonic regions. Bmp5, Bmp7 Ectoderm Unresolved issues Nog, Chrd, Cer1 Although some aspects of the Shh, Bmp7 molecular basis of organizer activity Spry2, Fgf4, Fgf5, Fgf8, Frzb1, Wnt3, Wnt3a are now known, several issues Wnt7a, Wnt8 Gsc regarding the origin and identity of the EGO and the node remain Mesoderm unresolved.