Models for Patterning Primary Embryonic Body Axes: the Role of Space and Time
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This is a reformatted version of an article appeared in Seminars Cell Dev. Biol. 2015 doi:10.1016/j.semcdb.2015.06.005 Models for patterning primary embryonic body axes: the role of space and time Hans Meinhardt Max Planck Institute for Developmental Biology Spemannstr. 35, D- 72076 Tubingen¨ http://www.eb.tuebingen.mpg.de/meinhardt; [email protected] Models for the generation and interpretation of spa- Development of a higher organism starts, as a rule tial patterns are discussed. Crucial for these pro- with a single cell and proceeds, of course, under the cesses is an intimate link between self-enhancing control of genes. Since the genetic material is es- and antagonistic reactions. For spatial patterning, sentially the same in every cell, a central question is long-ranging antagonistic reactions are required how the correct arrangement of differentiated cells is that restrict the self-enhancing reactions to gener- achieved. A most important step on the way from the ate organizing regions. Self-enhancement is also fertilized egg to an adult organism is the setting up of required for a permanent switch-like activation of the primary body axes, anteroposterior (AP) and medi- genes. This self-enhancement is antagonized by olateral/ dorsoventral (DV). In this process, organizing the mutual repression of genes, making sure that in regions - small nests of cells that act as sources or a particular cell only one gene of a set of possible sinks of signalling molecules - play an important role. genes become activated - a long range inhibition in The Spemann organizer is a prominent example. This the ‘gene space’. The understanding how the main organizer is usually regarded as the only organizer that body axes are initiated becomes more straightfor- exists in vertebrates, raising the question how a sin- ward if the evolutionary ancestral head/brain pat- gle organizer can specify the cells along the two ma- tern and the trunk pattern is considered separately. jor body axes that are oriented perpendicular to each To activate a specific gene at particular concentra- other. Moreover, DV patterning has to occur along the tion of morphogenetic gradient, observations are long extended AP axis. This task cannot be accom- compatible with a systematic and time-requiring plished by a patch-like organizer directly. A local sig- ‘promotion’ from one gene to the next until the lo- nalling source would lead to a conical positional infor- cal concentration is insufficient to accomplish a mation profile with a constant slope into all directions, further promotion. The achieved determination is which is clearly insufficient to specify the DV axis. Mod- stable against a fading of the morphogen, as re- els will be discussed that account for the generation quired to allow substantial growth. Minor modifi- and alignment of the main body axes. cations lead to a purely time-dependent activation The formation of organizing regions requires in- of genes; both mechanisms are involved to pattern teractions in which local self-enhancement and long- the anteroposterior axis. A mutual activation of cell range inhibition is involved, discussed in detail else- states that locally exclude each other accounts for where [1, 2, 3]. The interaction of the self-enhancing many features of the segmental patterning of the Nodal with the antagonistically acting Lefty is an exam- trunk. A possible scenario for the evolutionary in- ple [4, 5]. Such interactions can generate patterns in vention of segmentation is discussed that is based an initially homogeneous assembly of cells. For em- on a reemployment of interactions involved in asex- bryos that start with a large size such as the amphibian ual reproduction. embryo, the employment of maternal determinants is an appropriate strategy. By making only a small part of the embryo competent for organizer formation, local- Key words: Pattern formation / gene activation / seg- ized determinants only allow a single organizer to be mentation / main body axes / interpretation of gradients formed. Maternal determinants are not required if de- velopment starts as a small nest of cells such as it is the case in mouse or chick development. In this case, 1 the self-regulatory features of pattern-forming reactions induce neuronal tissue in the overlying ectoderm [13]. allow complete development in fragments even if the The prechordal plate is the precondition to form the organizer is removed [6]. The formation of several em- midline, the dorsal-most structure from which the dis- bryos after early fragmentation of a chicken embryo is tance of the cells is measured, so to say, a reference an example [7]. line. In contrast, for midline formation of the trunk, cells The generation of organizing regions requires com- near the blastopore (marginal zone) move towards the munication between cells. If based on diffusion, the organizer (node), causing a conversion a ring perpen- range of this signalling is restricted to short distances. dicular to the AP axis into a rod-like structure parallel to Thus, these patterns can only be generated at small the AP axis. This process will be discussed further be- scales during early stages of development and have low in more details. The two very different functions of to be converted into a pattern of stable cell determi- the organizer become established very early by a sub- nations by activating particular genes. The activities of division into a head- and a tail-organizer [14]. these genes have to be maintained even if the evok- Frequently the Spemann-organizer is assumed to ing signals are no longer available. Complementary to provide the positional information for organizing the AP models for setting up positional information for the body axis [14]. In the view of the model proposed, this con- axes, models for the stable activation of genes under clusion is partially misleading and results from the fact the influence of the resulting signal distributions will be that most AP-markers are absent if the organizer is discussed. It will be shown that activation of the correct missing. However, most of these markers are neu- gene at a particular position is a time-requiring process. ronal markers that disappear if no midline is formed. Thus, the loss of anterior AP markers in the absence 1. Axes formation in two steps: the head and of the organizer is caused by a non-functional DV pat- the trunk terning. In this relation a very instructive set of ex- periments has been done by Ober and Schulte-Merker Understanding of the patterning along the main body in the zebra fish [15]. By removing required mater- axes of vertebrates is much facilitated if it is realized nal components, they obtained embryos reliably devoid that different mechanisms are involved in patterning the of any organizer. To visualize the AP patterning they head and in the trunk. This is true for both the pattern- removed all BMP signalling, allowing in this way the ing along the AP and the DV axes. Several observa- expression of neuronal markers. Genes like Otx and tions suggest that the AP pattern in the brain is under Krox20 were expressed at nearly normal positions but control of a Wnt gradient that is generated at the blasto- in a completely radially-symmetric way, illustrating that pore/marginal zone [8, 9, 10]; (reviewed in [11]). The the activation of the anterior AP genes do not require region of forebrain formation has the largest distance to the organizer. However, as discussed further below, the blastopore and emerges at a low WNT concentra- the organizer plays a crucial role in the AP patterning tion, suggesting that the forebrain is the default state. of the trunk by terminating the time-dependent posteri- Thus, the first steps in the AP patterning of the brain orization. can be regarded as an example where a morphogen gradient accomplishes posteriorization by gene activa- 2. The separation of axes formation into a tion in a concentration- and thus position-depending brain- and a trunk-part has an evolutionary manner. In contrast, the AP patterning of the trunk is achieved by a sequential posterior elongation. In cells justification close to the blastopore but with the exemption of the or- Coelenterates are assumed to represent a basal ganizer region, new Hox genes become activated in a branch of the metazoan evolutionary tree. A com- sequential way, causing specification of more and more parison of the gene expression patterns in the posterior structures - a time-dependent process [12]; radial-symmetric freshwater polyp Hydra - a much- (Durston and Zhu, this issue). Although both mecha- investigated Coelenterate - and homologous genes in nisms overtly look very different, as shown below, mod- higher organisms suggested that the body column of elling revealed that gene activation under the influence an ancestral sac-like creature with a single opening of a static gradient has also a strong time-dependent evolved into the brain of higher organisms; the ances- component, suggesting that interpretation of a gradient, tral oral-aboral pattern evolved in the head/brain AP- e.g., in the brain and the time-dependent posterioriza- pattern [16]. Wnt and Brachyury are expressed at the tion in the trunk shares common elements. tip of the hypostome and at the most posterior region Pronounced differences between brain and trunk in higher organisms, suggesting that, in contrast to patterning also exist for the patterning of the DV axis. a na¨ıve expectation, the so-called Hydra head is the For the patterning of amphibian brain it is crucial that most-posterior structure, corresponding to the blasto- cells derived from the Spemann organizer move under- pore in higher organisms (Fig. 1). This view is sup- neath the ectoderm, forming the prechordal plate and 2 Fig.