Evolution of vertebrate forebrain development: how many different mechanisms?

Over the past 50 years and more, many models have been proposed to explain how the nervous system is initially induced and how it becomes subdivided i nto gross regions such as forebrain, midbrain, hindbrain and spinal cord. A mong these models is the 2-signal model of Nieuwkoop & Nigtevecht (1954), w ho suggested that an initial signal ('activation') from the organiser both neuralises and specifies the forebrain, while later signals ('transformatio n') from the same region progressively caudalise portions of this initial t erritory. An opposing idea emerged from the work of Otto Mangold (1933) and other members of the Spemann laboratory: 2 or more distinct organisers, em itting different signals, were proposed to be responsible for inducing the head, trunk and tail regions. Since then, evidence has accumulated that sup ports one or the other model, but it has been very difficult to distinguish between them. Recently, a considerable body of work from mouse embryos has been interpreted as favouring the latter model, and as suggesting that a ' head organiser', required for the induction of the forebrain, is spatially separate from the classic organiser (Hensen's node). An extraembryonic tiss ue, the 'anterior visceral endoderm' (AVE), was proposed to be the source o f forebrain-inducing signals. It is difficult to find tissues that are dire ctly equivalent embryologically or functionally to the AVE in other vertebr ates, which led some (e.g. Kessel, 1998) to propose that mammals have evolv ed a new way of patterning the head. We will present evidence from the chic k embryo showing that the hypoblast is embryologically and functionally equ ivalent to the mouse AVE. Like the latter, the hypoblast also plays a role in head development. However, it does not act like a true organiser. It ind uces pre-neural and pre-forebrain markers, but only transiently. Further de velopment of neural and forebrain phenotypes requires additional signals no t provided by the hypoblast. In addition, the hypoblast plays a role in dir ecting cell movements in the adjacent epiblast. These movements distance th e future forebrain territory from the developing organiser (Hensen's node), and we suggest that this is a mechanism to protect the forebrain from caud alising signals from the node. These mechanisms are consistent with all the findings obtained from the mouse to date. We conclude that the mechanisms responsible for setting up the forebrain and more caudal regions of the ner vous system are probably similar among different classes of higher vertebra tes. Moreover, while reconciling the two main models, our findings provide stronger support for Nieuwkoop's ideas than for the concept of multiple org anisers, each inducing a distinct region of the CNS.