The Bone Morphogenic Proteins (BMPs) were found to be mediators of a suppressive signal- Xenopus cells were engineered to express a truncated BMP receptor, so that BMP signalling was blocked. The cells with the altered receptors differentiated into neural tissue, and so blocking BMP is sufficient to trigger neural differentiation from ectodermal cells.
It was then postulated that the organiser region acts by blocking BMP- hence allowing neural tissue differentiation. The supporting evidence for this theory comes from the identification of Noggin, Follistatin, and Chordin- three major proteins found in the organiser region cells, and able to bind BMPs and inhibit their activity.
It is transcription factors from the Sox gene family that appear to play a role in differentiation of neural plate cells.
Once the cells have been induced as neural, their further fate is controlled by two systems- that controlling the dorso-ventral axis; and that controlling the rostro-caudal axis.
Dorso-ventral patterning
When looking at a spinal cord cross-section, it is possible to see clearly a dorsal half (neurons of which are involved in sensory processing), and a ventral half (neurons involved in motor output).
The ventral floor and dorsal roof plates are formed from specialised glial cells.
Inducing signals from the organiser region and notochord act locally and long-range, to induce ventral floor plate and motor neuron and interneuron differentiation respectively). Once the ventral floor plate has been induced, it takes over from the notochord, with the same signalling.
Both the local and long-ranged signalling activities are mediated by Shh (sonic hedgehog)- a potent secreted protein that can induce differentiation of ventral floor plate cells, motor neurons and ventral interneurons, all by itself.
By making Shh knockouts, one can block the ability of the notochord to induce virtually all cell types in the ventral neural tube. Thus this one protein is both necessary and sufficient for induction of most cell types generated in the ventral half of the neural tube.
So how does Shh determine the fate of so many different cell types in the ventral half of the CNS? Well, it can act both as an inducer, and a morphogen (inductive signals that can direct different cell fates at different concentration thresholds). So, at low concentrations of Shh, ventral interneurons are induced. Higher concentrations cause motor neurons to be induced, and even higher Shh concentrations causes the induction of a ventral floor plate.
It would be plausible, with Shh being such a potent signalling molecule, that dorsal neural tube patterning would also be induced by Shh, or perhaps by the lack of it (i.e. default pathway). However, a separate class of factors has been elucidated in induction of dorsal cell differentiation. These are the BMPs (same family as those involved in control of neural induction). Dorsal patterning seems to involve several members of the BMP family- each of which may induce a particular set of cells.
Patterning of both halves of the neural tube is similar in that inductive signals for both are initially expressed by non-neural cells (epidermal ectoderm and notochord for dorsal and ventral respectively). The process may be described as homeogenetic induction- like begets like- in that signals are transferred to specialised glial cells (floor plates), ensuring future cellular sources of inductive signals are in appropriate places to control cell fate and pattern at later stages of development.
Dorsoventral patterning is controlled in the same way in the rostral neural tube- the brain region. Shh secreted from the ventral floor plate acts on progenitor cells in the mesencephalic areas (future midbrain) to generate dopaminergic neurons of the substantia nigra and ventral tegmental areas. There is thus a possible role of Shh signalling in Parkinson’s Disease treatment- if Shh appears to play a role in the generation or regeneration of dopaminergic neurons.
The exception to this continued rostrocaudal pattern is at the rostral diencephalon and telencephalon, both Shh and BMPs are expressed by the axial mesoderm- it appears the source of BMP signals has been translocated from dorsal to ventral location (from epidermal ectoderm to pre-notochordal mesoderm).
Rostro-caudal patterning
The patterning of neural tissue along this axis is linked with neural induction, and occurs when the nervous system is still at the neural plate stage.
Neural tissue induced by follistatin, noggin and chordin expresses genes characteristic of the forebrain, but not of the more posterior (caudal) neural tissue (e.g. midbrain, hindbrain, spinal cord).
The Fibroblast Growth Factor (FGF) family of secreted proteins may play a role in the induction of these more posterior tissues, and an unrelated molecule, retinoic acid, has the ability to induce posterior neural tissue, which is characteristic of the spinal cord and hindbrain.
The specificity of neuronal connections is a remarkable physical feature of the nervous system. The correct guidance of axons from their points of origin to their appropriate targets is fundamental to a healthy, effective nervous system. The way axons achieve this with such extraordinary, perfect accuracy is surely something to marvel at, especially when one considers the considerable distance some axons must grow, bypassing targets along the way, to make connections with functionally appropriate synaptic partners.
So how do axons do it?
There are a number of techniques employed by the nervous system to ease the pressure: some axons crawl along epithelial or extracellular surfaces, and sometimes ‘guidepost’ cells mark sites where axons must make divergent choices. Some axons that grew earlier in development, when distances were shorter, can pioneer routes, which growth cones of newer axons may follow, by cell-cell adhesion. There are two important classes of molecules involved in this latter method- N-CAM (of the superimmunoglobulin family) and N-Cadherin (of the Ca++-dependent cadherin family). Both of these molecules are generally present on the surfaces of growth cones, axons, glial cells, muscle cells, and other cell types growth cones may crawl over.
I mentioned the growth cone- this is a spiky enlargement of the tip of the process, and is responsible for guiding the neurite to the correct position. The growth cone acts as both a sensory and motor structure. It puts out filopodia and lamellipodia to sense the environment in which it is growing, and these projections may retract if unfavourable conditions are contacted, or persist if favourable. The growth cone has a multitude of receptors, which allow accurate detection of external signals. It also possesses cytoskeletal proteins and actin-based motors that propel it forward.
The discoveries made about neurite guidance are making for exciting times in this extraordinary field of neuroscience, and have broad application in the field of neuro-medicine.