Funding for this site is provided by readers like you.
How the mind develops

From Embryo to Ethics

Help Link : Axon Guidance

Proteins That Guide the Wiring of the Brain

Each neuron also sends out dendrites that will eventually let it receive contacts from other neurons. Dendrites are extensions from the cell body that are shorter than axons and are highly ramified (branched). Like axons, dendrites grow by extending growth cones at their tips.


Probably one of the most amazing things about the way the nervous system develops is how the growing axons find their target cells, even though these cells are often located millimetres or even centimetres away (a vast distance on this scale). The source of this ability is the growth cone, a structure at the tip of each elongating axon.

The growth ’cone is composed of various projections that extend and retract as they seek out signals to guide them, something like your fingers might if you were groping to explore your surroundings in the dark. By interacting in this way with its environment, each growth cone finds signals that guide it to the spot where it must establish connections with its target cells .

These guidance signals consist of molecules that tell the growth cone which direction to go. Some of these guidance molecules are attached directly to the substrate along which the growth cone moves. But other guidance molecules are secreted by cells and diffuse freely into the surrounding area. A concentration gradient thereby forms that remotely influences the path that the axon follows as it grows.

The reason that the growth cone can be influenced by these molecules is that it has special receptors to detect them. Thus it is through the deployment of guidance molecules and the distribution of specific receptors for them across various neurons that the major neural pathways are laid down in the embryo.


Proteins That Guide the Wiring of the Brain

There are over 100 billion neurons in the human brain, and each of them forms several thousand synapses with other neurons. The possible combinations thus greatly exceed the 20 000 or 30 000 genes in the human genome. This limited nature of the available genetic information suggests that other, extrinsic factors, such as chemoattractive molecules and interactions among cells, play a major role in the development of the nervous system.

Link : Recount slashes number of human genes Link : Scientists slash estimate of human genes Link : How Many Genes Are in the Human Genome?

The growth cone that guides the axon to a cell with which it must form a synapse is like someone driving a car through unfamiliar country with no road map and only the signs along the way as a guide. For the growth cone, these road signs take the form of molecules. These growth cone guidance molecules are divided into two major families.

The first family consists of molecules that are attached to various substrates along the path that the growth cone travels. Like signs that a driver recognizes alongside the road, these cell adhesion molecules are recognized by specific receptors on the growth cone’s membrane.

As the result of direct contact between the cell adhesion molecules and their receptors on the axon’s growth cone, other signals are transmitted to the inside of the growing axon. These signals ultimately set the direction in which the axon grows. In contrast to the other family of guidance molecules, cell adhesion molecules are described as “non-diffusible”.


Dr. Brian E. Staveley
Department of Biology
Memorial University of Newfoundland
Growth cone changing direction after touching a substrate with compatible cell adhesion molecules

The second family of axon guidance molecules are not attached to a substrate. Instead, they diffuse freely into the aqueous environment surrounding the growth cone. The mechanism by which these diffusible molecules guide the growth cone is called chemotropism. Some of these molecules guide the growth cone by attracting it, the way the smell of freshly brewed coffee pulls a coffee lover toward the shop where it is being brewed. This kind of chemotropism is called “chemoattraction”. But there are also some guidance molecules that repel the growing axon, just as foul odours from a landfill might repel someone walking by. This kind of chemotropism is called “chemorepulsion”.

Lastly, there is a third category of molecules that do not provide guidance signals as such but are nevertheless necessary for the elongation of the axon. These molecules are called growth factors, and they play a crucial role in the formation of synaptic connections.


Original modules
Tool Module: Apoptosis (Programmed Cell Death) Apoptosis (Programmed Cell Death)

In addition to allowing certain neurons to survive during development and then participate in organizing their initial connections, the competition for trophic molecules allows the neurons’ ramifications and connections to change throughout the individual’s lifetime, in response to changes in neural activity caused by learning processes.


From the moment that the neurons start to form circuits, a change of scale takes place in the nervous system’s development—from isolated cells to a network of thousands of interconnected elements. It is this network that develops the information-processing capacity that makes the brain such a powerful tool.

But initially, this network is far from perfect. At first, the embryo produces two to three times more neurons than it needs. Subsequently, the excess neurons die off. So which neurons survive, and why?

We now know that a neuron’s survival depends largely on the relationship that it maintains with its target cell. For example, experiments have shown that reducing the number of target cells reduces the number of neurons that have to come connect to them. Conversely, the existence of a larger population of cells that have to be innervated keeps a larger number of innervating neurons alive.

The survival rate of neurons depends on the size of the population of target cells that they innervate. The shaded areas here represent the destruction of target cells.

The mechanism at work here involves a certain competition among the neurons for special substances known as growth factors or trophic factors (from the Greek trephein, meaning “to nourish”). These factors are not energy sources like glucose or ATP. But they are molecules that are secreted by the target cells and that the neurons must have in order to survive.

To use an automobile metaphor again, these factors are not the gasoline that the car uses as its energy source; they are more like the driver’s licence. The absence of growth factor leads to major problems in the development of an axon and very often to its outright removal from the neural highway.

The way neurons die in such circumstances is quite different from their death due to injury or illness. Instead it is a gradual, programmed form of death, known as apoptosis.

Apoptosis involves the expression of a multitude of specific genes that make cells decay in a way that does not harm the organism as a whole. These same genes are also often involved in cell differentiation and in controlling the normal cell life cycle. (For more about apoptosis, follow the Tool module link at the start of this section.)

In addition to this competition within populations of neurons as a whole, there is another form of competition among the various axons that innervate the same embryonic cell.


Link : La connaissance de la génétique de l'autisme avance

The neurons in a baby’s brain receive about one and a half times more synapses than those in an adult’s. It is thought that the number of these myriad connections remains fairly constant until puberty, but declines markedly during adolescence. For example, during adolescence, the neurons of the primary visual cortex are believed to lose an average of 5 000 synapses per second!

The process whereby a target cell loses connections from several neurons and retains connections from only one is often inaccurately referred to as synapses’ being eliminated. It would be more accurate to say that there is a reduction in the number of different afferences that the target cell receives. The total number of synapses generally does nothing but increase over the course of development.


Often, the axons of neurons that will ultimately be part of different neural circuits are guided along the same path until they reach the vicinity of their target cells. But how does each axon then recognize its own target cell?

In some cases, molecules similar to cell adhesion molecules seem to act as labels that let the various axon growth cones recognize the right target cells. In addition, the exact location where the axon forms its synapse with the cell is closely controlled by a particular set of molecules, because the synapse requires the presence of particular molecular structures in order to function properly.


In a neuromuscular junction (the type of synapse whose formation process has been studied the most), this location is called the “active zone”. Here the axon’s machinery for releasing neurotransmitters from the motor neuron aligns with very dense groups of acetylcholine receptors in the muscle fibre.

Initially, one muscle fibre may receive connections from several motor neurons. But gradually, it will lose all but one of these junctions and remain connected to only one motor neuron.

Researchers have shown that this process is regulated by the electrical activity in the muscle fibre. The more active the fibre, the more quickly synapses are eliminated, except for those from the one motor neuron that will remain . Conversely, reducing the muscle fibre’s activity slows down this selection process.

There is ample evidence that such synaptic reorganizations also occur in the immature brain. A given neuron may lose connections that it had initially established with other neurons, or it may see its connections with certain neurons multiply. Here again, it is neural activity that maintains or increases the number of synaptic contacts, while the absence of stimulation leads to the elimination of synapses that are unneeded. That is why the stabilization of the synapses is regarded as a selective process and why the activity of the neural circuits is regarded as controlling this selection.

The connections among the neurons of the human brain are initially determined by an inherited genetic map. Subsequently, these connections are remodelled through the individual’s interactions with the environment. Two major types of information pathways then develop: converging pathways, in which multiple nerve fibres connect to the same target cell, and diverging pathways, in which a single neuron connects to several different cells.

  Presentations | Credits | Contact | Copyleft