Abstract
Recent studies have demonstrated that the topography of thalamocortical (TC) axon projections is initiated before they reach the cortex, in the ventral telencephalon (VTel). However, at this point, the molecular mechanisms patterning the topography of TC projections in the VTel remains poorly understood. Here, we show that a long-range, high-rostral to low-caudal gradient of Netrin-1 in the VTel is required in vivo for the topographic sorting of TC axons to distinct cortical domains. We demonstrate that Netrin-1 is a chemoattractant for rostral thalamic axons but functions as a chemorepulsive cue for caudal thalamic axons. In accordance with this model, DCC is expressed in a high-rostromedial to low-caudolateral gradient in the dorsal thalamus (DTh), whereas three Unc5 receptors (Unc5A–C) show graded expression in the reverse orientation. Finally, we show that DCC is required for the attraction of rostromedial thalamic axons to the Netrin-1–rich, anterior part of the VTel, whereas DCC and Unc5A/C receptors are required for the repulsion of caudolateral TC axons from the same Netrin-1–rich region of the VTel. Our results demonstrate that a long-range gradient of Netrin-1 acts as a counteracting force from ephrin-A5 to control the topography of TC projections before they enter the cortex.
Highlights
In the central nervous system, the vast majority of axonal projections are organized topographically
How is the complex topography of thalamic axon projection to individual cortical areas specified during development? Recent evidence demonstrated that thalamic axons are routed to different cortical domains before they enter the cortex, by putative axon guidance cues present in the ventral forebrain
We provide evidence that a secreted axon guidance cue, Netrin-1, expressed in a long-range gradient in the ventral forebrain, plays a critical role in the establishment of the topography of thalamic projections by directing different subsets of axons to specific cortical domains
Summary
In the central nervous system, the vast majority of axonal projections are organized topographically. Each thalamic nucleus projects topographically to a unique set of cortical areas (interareal, first-order level of topography), and subsequently, axons emerging within a given thalamic nucleus establish a topographic map of a given sensory modality within each cortical area (intra-areal, second-order level of topography). Genetic manipulation of rostral patterning molecules such as FGF8 affects the relative positioning of cortical areas without initially changing the topography of TC projections to the appropriate ‘‘cortical domain’’ [7,8]. These findings suggested a model in which TC axons are guided to their appropriate cortical domain by extracortical cues, i.e., before reaching the cortex. At later stages, unidentified cortical cues are able to redirect thalamic axon outgrowth to the appropriate cortical area inside the cortex proper [8], a result found in heterotopic cortical grafting experiments [9]
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