Signaling Mechanisms of Axon Guidance and Early Synaptogenesis

Abstract

The development of the vertebrate nervous system, including the brain and spinal cord, progresses in a step-wise fashion that involves the function of thousands of genes. The birth of new neurons (also known as neurogenesis) and their subsequent migration to appropriate locations within the developing brain mark the earliest stages of CNS development. Subsequently, these newborn neurons extend axons and dendrites to make stereotyped synaptic connections within the developing brain, which is a complex process involving cell intrinsic mechanisms that respond to specific extracellular signals. The extension and navigation of the axon to its appropriate target region in the brain and body is dependent upon many cell surface proteins that detect extracellular cues and transduce signals to the inside of the cell. In turn, intracellular signaling mechanisms orchestrate axon structural reorganization and appropriate turning toward or away from a guidance cue. Once the target region is reached, chemical synapses are formed between the axon and target cell, and again, this appears to involve cell surface proteins signaling to the inside of the neuron to stabilize and mature a synapse. Here, we describe some of the key convergent and, in some cases, divergent molecular pathways that regulate axon guidance and synaptogenesis in early brain development. Mutations in genes involved in early brain wiring and synapse formation and pruning increase the risk for developing autism, further highlighting the relevance of brain development factors in the pathophysiology of neurodevelopmental disorders.

Influence of maternal thyroid hormones during gestation on fetal brain development

“…Outgrowing axons are able to make use of the scaffold formed by earlier axons, so-called pioneers, giving rise to axon fascicles that form the neural circuitry (Robichaux and Cowan, 2014). Synaptogenesis accelerates in the third trimester to approximately 40,000 synapses per minute (Bourgeois, 1997), and around mid-gestation the process of myelination of the axons begins, allowing for more efficient cell-to-cell communication (Abraham et al, 2010).…”

Circuit development in the master clock network of mammals

“…Newly differentiated neurons undergo elongation of axonal and dendritic processes, ultimately culminating in the genesis of synapses (Robichaux & Cowan, ; Tretter & Moss, ). These two interrelated stages are orchestrated by a variety of mechanisms (e.g., signalling gradients, contact receptors, and cell adhesion molecules), which prompt reorganization of the cytoskeletal proteins actin and tubulin in developing neurons.…”

Autophagy in synaptic development, function, and pathology

“…Synaptogenesis is a multistep process, and a variety of molecules and signaling pathways have been identified to mediate early synaptogenesis [12] . Autophagy and the ubiquitin-proteasome system are major pathways for protein degradation in cells.…”