Target Selection

General Target Selection

The initial part of the lecture examines general target selection, highlighting factors guiding axons to their intended destinations. These factors include:

  • Chemoattractants: Molecules like Netrin, acting through receptors like Frazzled, attract growing axons towards specific targets. Mutations in these pathways lead to targeting errors.

  • Chemorepellents: Molecules like Semaphorins and Ephrins repel axons from certain regions, preventing them from innervating incorrect targets.

  • Growth Factors:  Fibroblast Growth Factor 2 (FGF2) and neurotrophins guide axons, potentially by creating concentration gradients that axons follow.

The lecture emphasizes the importance of combinatorial coding in target selection. Axons encounter a complex environment with overlapping cues; their response depends on the combination of cues present and their relative levels. For instance, Drosophila motor neurons utilize a combination of Netrin, Connectin, Fasciclins, and Semaphorins to target specific muscle fibers.

Targeting Multicellular Structures & Barriers

Beyond individual targets, axons also navigate to larger structures. Examples include:

  • Retinal axon targeting: Retinal Ganglion Cells (RGC) axons accurately target specific layers within the Lateral Geniculate Nucleus (LGN), crucial for visual processing.

  • Neurotrophins' role: Neurotrophins, like NT-3, act as chemoattractants, guiding axons to specific targets. For instance, NT-3 is critical for the sympathetic innervation of the external ear.

The lecture then discusses how axons are prevented from entering restricted areas:

  • Formation of Barriers:  Ephrins can establish repulsive barriers, restricting axons to specific regions. Disrupting these barriers allows axons to innervate otherwise inaccessible targets.

Topographic Mapping

The lecture transitions to topographic mapping, a fundamental principle in sensory systems, ensuring an ordered representation of the external world in the brain. Examples include:

  • Visual System: Retinal axons project to the Superior Colliculus (SC) in a topographically organized manner, preserving spatial relationships between the retina and the SC.

  • Somatosensory System: The somatotopic map in the neocortex represents the body surface, with adjacent body parts mapped to nearby cortical regions.

  • Olfactory System: Olfactory sensory neurons expressing the same odorant receptor project to specific glomeruli in the olfactory bulb, creating an odor map.

The lecture focuses on the retinotectal projection to illustrate the establishment of point-to-point specificity in topographic maps. It addresses several hypotheses, ultimately supporting a chemospecificity model based on Ephrinsignaling:

  1. Axonal Associations in Optic Tract: This hypothesis proposes that axons maintain their relative positions within the optic nerve and tract. However, experiments like the "double-ventral" retina transplantation demonstrate that this is not the case.

  2. Timing of Axonal Ingrowth: This hypothesis suggests that the order of RGC axon arrival determines their target locations. Heterochronic retina transplant experiments disprove this idea, showing that axons find their appropriate targets despite arriving at different times.

Sperry's Chemospecificity Hypothesis: This hypothesis, supported by experimental evidence, suggests that gradients of molecules on both the retina and the tectum guide axons to their specific targets.

  • Sperry's Experiment: Rotating the eye and allowing the optic nerve to regenerate led to axons re-establishing connections based on their original retinal positions, not their new orientations. This indicates a chemical guidance mechanism rather than a random reconnection.

Molecular Mechanisms of Chemospecificity:

  • Ephrins and Gradients:  Ephrin A molecules, concentrated in the posterior tectum, repel axons originating from the temporal retina, establishing an anterior-posterior axis in the map.

  • Bidirectional Signaling: Ephrins can signal bidirectionally, acting as either ligands or receptors. In the retinotectal system, Ephrin B molecules mediate attractive interactions, contributing to the dorsal-ventral axis of the map.

Summary: Retinotopic Maps

  • Ephrin gradients establish a coarse topographic map in the SC.

  • Ephrins can function as both repulsive and attractive cues, guiding axons along both axes of the map.

In conclusion, Lecture 11 provides a comprehensive overview of target selection, covering molecular cues, mechanisms, and the crucial concept of topographic mapping. The lecture underscores the importance of combinatorial signaling, gradients, and specific molecular interactions in establishing precise neuronal connections during development.