Axonal pathfinding during the development of the nervous system.

Guidance of axons sprouting from maturing neuroblasts, during intermediate trajectories and in seeking target neurons for synaptogenesis, is a fundamental developmental process in central nervous system maturation. Axons but not dendrites sprout from neuroblasts during migration. The growth cone of the axonal tip projects constantly changing multiple veils and spikes (lamellipodia and filopodia) that contain microtubules, actin microfilaments, mitochondria, endosomes, and membrane receptor proteins. They are sensitive to changes in ionic calcium flux and may be impeded by perinatal hyper- or hypoglycemia. The growth of axonal membranes occurs mainly at the growth cone. Neurofilaments appear in the axonal tip as it approaches its target. Growth cones are attracted to or repelled by various extracellular matrix molecules that guide them, such as netrins and glycoproteins. Numerous genes are involved, some specific for only certain projections. Neurotransmitters later to be secreted are recognized in growing axons before their synthesis. Axonal fascicles are enveloped by extracellular keratan sulfate that ensures that fascicles contain axons of similar origin and destination and whose neurons secrete the same transmitter. Near their targets, axonal tips may ramify to form synapses on more than one neuron. Transitory pioneer axons provide supplementary mechanical guides to permanent axonal trajectories. Thalamus and olfactory bulb contain axonless neurons with dendrodendritic synapses. Chromaffin neurons of neural crest origin develop no neurites. Most cerebral malformations involve aberrant axonal pathfinding; in holoprosencephaly, keratan sulfate abnormally ensheathes individual axons. Axonal pathfinding to near or distant target neurons is primordial for synaptic circuitry subserving normal and abnormal neurological functions including epilepsy.