Axonal pathfinding during the development of the nervous system

Abstract

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.I consider primitive nerve fibres to be protoplasmic outgrowths of the central nerve cell.

Abnormal axonal development and severe epileptic phenotype in Dynamin‐1 (DNM1) encephalopathy

“…16 Generally, axonal growth requires neurofilaments and microtubules, which are produced within the neuron and transported distally by axoplasimic flow. 16 The corticospinal tract is typically bilateral at birth and progresses to a predominantly unilateral crossed projection in early childhood. 17 Therefore, the decreased pyramidal decussation in this case may indicate that the formation of axons and synapses was impaired by the DNM1a variant and that motor neurons running in the corticospinal tract did not develop normally.…”

“…Axonal pathfinding has progressed not only during embryonic period but also after birth. Moreover, fetal and neonatal hypocalcemia is known to impair axonal growth and synapse synaptogenesis, resulting in clinical symptoms 16 . Generally, axonal growth requires neurofilaments and microtubules, which are produced within the neuron and transported distally by axoplasimic flow 16 .…”

Developmental milestones as ACNS turns one year old

“…The first article after the opening editorial was Harvey Sarnat's eloquent review of axonal pathfinding and guidance in the development of the nervous system, a basic science topic with obvious clinical relevance. 2 Curtis Coughlin and Sidney Gospe contributed an outstanding summary of pyridoxine dependency. 3 These authors were instrumental in unraveling the clinical features, genetics, and molecular mechanisms of pyridoxine dependency, so not surprisingly, their review is a tour de force.…”

“…The initial ACNS articles have been remarkably good, led by a series of excellent review articles by pioneers in the field. The first article after the opening editorial was Harvey Sarnat's eloquent review of axonal pathfinding and guidance in the development of the nervous system, a basic science topic with obvious clinical relevance 2 . Curtis Coughlin and Sidney Gospe contributed an outstanding summary of pyridoxine dependency 3 .…”

Sequences of synaptogenesis in the human fetal and neonatal brain by synaptophysin immunocytochemistry

“…Synaptogenesis is fundamental to nervous system circuitry and networks that are the basis of functional expression. Though the concept had been expressed decades earlier (Ariëns Kappers, 1917), chemotropic guidance of axons to their target neurons for synapse formation was better understood in the 1980s (Brown et al, 2001;Rao and Jacobson, 2005;Sarnat, 2023). The final phase of axonal pathfinding as the axonal tip or growth cone approaches its target is terminal ramification of the growing axon and synapse formation on target neurons.…”