Transcriptional Control of Axon Guidance at Midline Structures

Abstract

The development of the nervous system is a time-ordered and multi-stepped process that includes neurogenesis and neuronal specification, axonal navigation, and circuits assembly. During axonal navigation, the growth cone, a dynamic structure located at the tip of the axon, senses environmental signals that guide axons towards their final targets. The expression of a specific repertoire of receptors on the cell surface of the growth cone together with the activation of a set of intracellular transducing molecules, outlines the response of each axon to specific guidance cues. This collection of axon guidance molecules is defined by the transcriptome of the cell which, in turn, depends on transcriptional and epigenetic regulators that modify the structure and DNA accessibility to determine what genes will be expressed to elicit specific axonal behaviors. Studies focused on understanding how axons navigate intermediate targets, such as the floor plate of vertebrates or the mammalian optic chiasm, have largely contributed to our knowledge of how neurons wire together during development. In fact, investigations on axon navigation at these midline structures led to the identification of many of the currently known families of proteins that act as guidance cues and their corresponding receptors. Although the transcription factors and the regulatory mechanisms that control the expression of these molecules are not well understood, important advances have been made in recent years in this regard. Here we provide an updated overview on the current knowledge about the transcriptional control of axon guidance and the selection of trajectories at midline structures.

Variability in Neural Circuit Formation

“…Rather than a one-to-one functional mapping between specific cue-receptor pairs and specific guidance decisions, this gives a view of a collective set of constraints that tend to channel growing neurons to their appropriate target re-gions and tend to direct synaptogenesis with the appropriate target cells or even the appropriate subcellular regions (Hiesinger 2021a,b). In turn, this landscape of cues and the respective repertoires of receptors are generated by a developmental program orchestrated by gene regulatory networks and patterning mechanisms involving dozens or hundreds of signaling proteins and transcription factors (Zarin et al 2014;Herrera and Escalante 2022).…”