Development of the Nervous System

Zygote - divides to form two daughter cells - two divide to form four - etc until a mature organism is produced Three other things must occur.

1. Cells must differentiate; some must become muscle cells, some must become multipolar neurons, some must become glial cells, and so on.
2. Cells must travel to appropriate sites and align themselves with the cells around them to form particular structures.
3. Cells must establish appropriate functional relations with other cells.

Accomplish these three things in five phases:
(1) induction of the neural plate
(2)neural proliferation
(3) migration and aggregation
(4) axon growth and synapse formation
(5) neuron death and synapse rearrangement.

A fertilized egg is totipotent - has the ability to develop into any class of cell in the body.

developing cells have the ability to develop into many (not all) classes of body cells.

As the embryo develops, new cells become more and more specialized.

Three weeks after conception - the tissue becomes recognizable as the neural plate.

Neural plate - a small patch of ectodermal tissue on the dorsal surface of the developing embryo.

Ectoderm, mesoderm, and endoderm - three layers of embryonic cells.

Development of the neural plate - first major stage of neurodevelopment. Induced by chemical signals from an area of the underlying mesoderm layer (organizer).

Embryonic stem cells - the cells of the neural plate.

Stem cells meet two specific criteria:

(1) almost unlimited capacity for self-renewal (if maintained in an appropriate cell culture)

(2) they have the ability to develop into many different kinds of cells—they are either totipotent(all), pluripotent(many but not all), or multipotent(more than one but limited).

Many neurons develop from glial cells.

Neural plate (folds) - neural groove (lips fuse) - neural tube.

Neural tube defects develop into severe birth defects of the CNS;

Inside of the neural tube - cerebral ventricles and spinal canal.

40 days after conception, three swellings are visible at the anterior end of the human neural tube; these swellings will develop into the forebrain, midbrain, and hindbrain.

Neural groove has fused to the neural tube - the cells begin to proliferate (increase greatly in number).
This neural proliferation does not occur simultaneously or equally in all parts of the tube.
Most cell division in the neural tube occurs in the ventricular zone—the region adjacent to the ventricle (the fluid-filled center of the tube).
Two organizer areas in the neural tube that control proliferation:
Floor plate - runs along the midline of the ventral surface of the tube.
Roof plate - runs along the midline of the dorsal surface of the tube.

Cells are created in the ventricular zone of the tube, lacking axons and dendrites - migrate to the appropriate target location.

Two factors govern migration in the developing neural tube: time and location. In a given region of the tube, subtypes of neurons arise on a precise and predictable schedule and then migrate together to their prescribed destinations.

Two kinds of cell migration: Radial migration - from the ventricular zone in a straight line toward the outer wall of the tube.

Tangential migration - occurs at a right angle to radial migration, parallel to the tube’s walls.

Two methods of migration: somal translocation and glia-mediated migration.

Somal translocation - an extension grows from the developing cell in the direction of the migration; seemingly exploring the immediate environment for attractive and repulsive cues as it grows. Then, the cell body itself moves into and along the extending process, and trailing processes are retracted.

Glia-mediated migration - when the period of neural proliferation is underway and the walls of the neural tube are thickening, a network of glial cells (radial glial cells), appears in the developing neural tube. Many cells engaging in radial migration do so by moving along the radial glial network.

Inside-out pattern - radial pattern of cortical development.

Many cortical cells engage in long tangential migrations to reach their final destinations.

The patterns of proliferation and migration are different for different areas of the cortex.

The neural crest - a structure situated just dorsal to the neural tube. Formed from cells that break off from the neural tube as it is being formed. Neural crest cells develop into the neurons and glial cells of the peripheral nervous system.

Numerous chemicals guide various classes of migrating neurons by either attracting or repelling them. These guidance molecules play a critical role in neurodevelopment because the brain cannot function normally unless each class of developing neurons arrives at the correct location.

Aggregation - align themselves with other developing neurons that have migrated to the same area to form the structures of the nervous system.
CAMs (cell-adhesion molecules) - are thought to mediate migration and aggregation, located on the surfaces of neurons and other cells. Cell-adhesion molecules have the ability to recognize molecules on other cells and adhere to them.
Elimination of just one type of CAM in a knockout mouse - devastating effect on brain development.
Gap junctions - points of communication between adjacent cells; the gaps are bridged by connexins (narrow tubes), through which cells can exchange cytoplasm.

Axon growth- after neurons migrated and aggregated into neural structures, for the nervous system to function, these projections must grow to appropriate targets.

Growth cone - amoeba-like structure at each growing tip of an axon or dendrite, which extends and retracts filopodia (fingerlike cytoplasmic extensions) as if searching for the correct route. Growth cones seem to be influenced by a series of chemical and physical signals along the route.

Pioneer growth cones—the first growth cones to travel along a particular route in a developing nervous system, presumed to follow the correct trail by interacting with guidance molecules along the route. Fasciculation - The tendency of developing axons to grow along the paths established by preceding axons. Much of the axonal development in complex nervous systems involves growth from one topographic array of neurons to another.

The topographic gradient hypothesis - axons growing from one topographic surface to another (e.g., the optic tectum) are guided to specific targets that are arranged on the terminal surface in the same way as the axons’ cell bodies are arranged on the original surface. The key part - the growing axons are guided to their destinations by two intersecting signal gradients.

Synaptogenesis (the formation of new synapses) - depends on the presence of glial cells (particularly astrocytes).
Astrocytes - extensive role in synaptogenesis by processing, transferring and storing information supplied by neurons. Any type of neuron will form synapses with any other type.
Retinal ganglion cells maintained in culture formed seven times more synapses when astrocytes were present.
Synapses formed in the presence of astrocytes were quickly lost when the astrocytes were removed.
Synapses that do not function appropriately tend to be eliminated.

Neuron death - when developing neurons fail to get adequate nutrition.

Necrosis - passive cell death.

Necrotic cells break apart and spill their contents into extracellular fluid, the consequence is potentially harmful inflammation.

Apoptosis - active cell death.

Apoptosis is safer than necrosis.

In apoptotic cell death, DNA and other internal structures are cleaved apart and packaged in membranes before the cell breaks apart. These membranes contain molecules that attract scavenger microglia and other molecules that prevent inflammation.

Dark side of apoptosis:

if genetic programs for apoptotic cell death are blocked, the consequence can be cancer;

if the programs are inappropriately activated, the consequence can be neurodegenerative disease.

What triggers the genetic programs that cause apoptosis in developing neurons?

Some appear to be genetically programmed for early death, death because of no external stimulus, or failure to obtain the life-preserving chemicals that are supplied by their targets.

Neurotrophins- life-preserving chemicals, promote the growth and survival of neurons, function as axon guidance molecules, and stimulate synaptogenesis.

Nerve growth factor (NGF) - was the first neurotrophic substance to be identified, isolated, and characterized. Founding member of the neurotrophins, a family of secreted growth factors responsible for the growth, survival, and developmental plasticity of neuronal populations in the vertebrate peripheral and central nervous system.