Evidence That Descending Cortical Axons Are Essential for Thalamocortical Axons to Cross the Pallial-Subpallial Boundary in the Embryonic Forebrain

Yijing Chen,David J Price,Thomas Pratt,Thomas Theil,Dario Magnani

doi:10.1371/journal.pone.0033105

Abstract

Developing thalamocortical axons traverse the subpallium to reach the cortex located in the pallium. We tested the hypothesis that descending corticofugal axons are important for guiding thalamocortical axons across the pallial-subpallial boundary, using conditional mutagenesis to assess the effects of blocking corticofugal axonal development without disrupting thalamus, subpallium or the pallial-subpallial boundary. We found that thalamic axons still traversed the subpallium in topographic order but did not cross the pallial-subpallial boundary. Co-culture experiments indicated that the inability of thalamic axons to cross the boundary was not explained by mutant cortex developing a long-range chemorepulsive action on thalamic axons. On the contrary, cortex from conditional mutants retained its thalamic axonal growth-promoting activity and continued to express Nrg-1, which is responsible for this stimulatory effect. When mutant cortex was replaced with control cortex, corticofugal efferents were restored and thalamic axons from conditional mutants associated with them and crossed the pallial-subpallial boundary. Our study provides the most compelling evidence to date that cortical efferents are required to guide thalamocortical axons across the pallial-subpallial boundary, which is otherwise hostile to thalamic axons. These results support the hypothesis that thalamic axons grow from subpallium to cortex guided by cortical efferents, with stimulation from diffusible cortical growth-promoting factors.

Highlights

The precise and often highly complex connectivity of nervous systems develops through the guidance of elongating axons along specific pathways at specific times
The strongest hypotheses for which there is both in vitro and in vivo evidence focus on the important guiding role of intermediate cells in the subpallium. These cells form a permissive corridor through which thalamic axons grow towards the pallium and they express gradients of guidance molecules such as Netrin-1 and Ephrin-A5 that maintain the topographic order of thalamic axons as they traverse this region [8,9,10,11,12]
We found that blocking cortical efferent development did not stop thalamic axons traversing the subpallium in an ordered way but did completely prevent them from crossing the pallialsubpallial boundary (PSPB) to enter the cortex

Summary

Introduction

The precise and often highly complex connectivity of nervous systems develops through the guidance of elongating axons along specific pathways at specific times. The strongest hypotheses for which there is both in vitro and in vivo evidence focus on the important guiding role of intermediate cells in the subpallium. These cells form a permissive corridor through which thalamic axons grow towards the pallium and they express gradients of guidance molecules such as Netrin-1 and Ephrin-A5 that maintain the topographic order of thalamic axons as they traverse this region [8,9,10,11,12]. On the descending axons of cortical neurons as a potential source of guidance for ascending thalamocortical axons navigating towards the cortex [2,4,14,15,16], but as yet there is no strong supporting in vivo evidence for this hypothesis

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Conclusion