After gamete fertilization, the zygote goes through a series of developmental stages over time, and as cell proliferation occurs, they specialize and group together, to form tissues and organs with specific functions. This process is complex and requires many factors to work in synchrony.
In the case of the nervous system, the neurons themselves must first specialize, before the higher structural organization of neural networks can form. Basically, the building blocks of the nervous system must first be made, before building can begin. This essay will explain firstly how neurons differentiate, and then how these neurons specialize into various functional areas throughout the brain and peripheral nervous system.
In the early embryonic stages, cell potency is very high; totipotent stem cells can differentiate into any cell type the blastocyst genome codes for, which then cleave into pluri/multipotent progenitor cells, which are more specific than stem cells, but can still differentiate into many types of cell. Each progenitor cell can differentiate into cells that belong to the same tissue or organ, but have a ‘target’ cell type, due to gene regulation. The first stage to forming a neuron cell is the patterning of these progenitor cells. Patterning is enabled by the release of signaling molecules, which when secreted, switch on specific transcription factors (TF). These proteins regulate the transcription of genes from DNA to RNA, which is the process that allows the creation of cell proteins, and thus, specialization. TF proteins bind to specific sections of DNA, to either promote or restrict the production of its protein, which means they control which genes are expressed in the cells. Combinations of TFs are used to ‘switch on or off’ genes in each dividing cell, which in turn creates cells with different combinations of gene expression, thereby creating cellular phenotypic differences. This process occurs in neuronal progenitor target cells, leading to ‘neuronal birth’, where the initial neuron cell body is formed.
After post-mitotic neuronal birth, the rest of the cell must form, to enable full function. As connectivity is key in the nervous system, neurons have long axonal ‘wires’, and large dendrite webs, to link areas of the brain. From the neuron cell body, migration/elongation occurs, and acts as the beginning of axon formation. The next step is axon pathfinding/guidance, where the cells send out axon strands, to find their correct target. These axons follow precise pathways, and are guided by chemical signals and genotype expression to enable effective connections between brain regions. Once the axons have connected, dendrite morphogenesis and synapse formation begin. Dendrites are protoplasmic branches on neurons, which increase electrochemical stimulation received, due to larger surface area. Synapses are the gaps between axon connections, where nerve impulses are transmitted through neurotransmitter diffusion in vesicles. There are many molecular mechanisms behind these two processes: dendrite morphogenesis is coded by the genome, and continues after birth and during early childhood; synapse formation is key in the development of specialized circuits, and are facilitated by cell adhesion proteins (neurexins and neuroligins), a huge versatility of synapses are created, NLGN1 forms excitatory synapses, NLGN2 inhibitory, and NLGN3 enables both excitatory and inhibitory function, and the varying forms of these proteins are determined by phosphorylation of NLGN.
These processes of neurogenesis are occurring simultaneously to thousands of cells in the developing zygote, and once the neurons reach a certain level of progress, they will start to organize and group, in a secondary layer of patterning. The neural tube is the embryonic precursor to the chordate nervous system and is patterned according to a grid of positional information, to enable spatial analysis. The grid uses the AV (anterior-posterior) and DV (dorsal-ventral) axes as means to analyze the different regions of the tube. Like neurogenesis, the organization of nervous system regions is regulated by secreted factors, which signal specific cortical regions of the tube. Different TFs are expressed in different areas of the developing nervous system, which cause the phenotypic diversity we see in the cortex. For instance: frontal cortex is associated with Sp8 and Pax6; anterior neural ridge with FGFs (fibroblast growth factors, mainly FGF2 and FGF8); sub pallium with SonicHedgehog; cortical hem with Wnts and BMPs; and sensory areas with Emx2 and COUP-TF1. As well as cell organization into functional group areas, like those listed above, neurons in the cortex are also aligned into layers, in a process called cortical lamination, which forms the isocortex/neocortex, mesocortex, and allocortex, the function behind these cortical layers is to transfer information from the ventricular area to the cortical plate in the most optimized way for the neuronal wiring. These methods, in combination with guiding inputs from thalamocortical and corticofugal axons, enable the majority of prenatal development of the nervous system.
A final point to remember is that nervous system development doesn’t stop after birth; further dendrite branching, synaptogenesis, myelination, and prefrontal cortex development are processes which can continue well into early adulthood, being shaped by the formation of skills and experiences throughout life. Nervous system plasticity and neuronal death/pruning of unused cells is a continuous process, which allows our brains to continue to specialize as we grow older, meaning our brains are uniquely formed to respond to our personal needs.
In conclusion, there is a huge number of mechanisms at work in the differentiation of neurons and forming of brain regions. There must be many different mechanisms, because there are so many neural regions, and each must be formed perfectly to ensure proper function. I believe the huge number of factors involved in these processes serves to represent just how complex the adult nervous system is, and the many steps it must go through to achieve functionality. Transcription factors play perhaps the most key role in the mechanisms of specialization, as they regulate gene expression and protein production in a variety of settings. There is thought to be ~ 1600 TFs in the human genome, each with specific function and cooperators (with which they can join and form protein complexes), which enables the expression and interpretation of our genome. Overall, mechanisms of secreted factors, gene regulation/transcriptomics, and life experiences determine the form and function of both neurons, and the nervous system as a whole.