The role of the diencephalon in the guidance of thalamocortical axons in mice

Abstract

Thalamocortical axons (TCAs) cross several tissues on their journey to the cortex. Mechanisms must be in place along the route to ensure they connect with their targets in an orderly fashion. The ventral telencephalon acts as an instructive tissue, but the importance of the diencephalon in TCA mapping is unknown. We report that disruption of diencephalic development by Pax6 deletion results in a thalamocortical projection containing mapping errors. We used conditional mutagenesis to test whether these errors are due to the disruption of pioneer projections from prethalamus to thalamus and found that, although this correlates with abnormal TCA fasciculation, it does not induce topographical errors. To test whether the thalamus contains navigational cues for TCAs, we used slice culture transplants and gene expression studies. We found the thalamic environment is instructive for TCA navigation and that the molecular cues netrin 1 and semaphorin 3a are likely to be involved. Our findings indicate that the correct topographic mapping of TCAs onto the cortex requires the order to be established from the earliest stages of their growth by molecular cues in the thalamus itself.

The role of FGF3 in the guidance of prethalamic GABAergic axons

“…However, at E4, no PV + prethalamic axons were found in the thalamus. Consistent with previous studies [25,27], anterograde DiI labelling and immunolabelling show that parallel prethalamic GABAergic axons protrude dorsally into the thalamus. Previous studies that prethalamic pioneer axons somehow help the passage of the TCAs across this region [27].…”

Pax6 loss alters the morphological and electrophysiological development of mouse prethalamic neurons

“…Misrouting of TCAs is a known phenotype of Pax6 -/mutant mice (Auladell et al, 2000;Pratt et al, 2000;Simpson et al, 2009;Price et al, 2012;Clegg et al, 2015;Feng et al, 2016;Quintana-Urzainqui et al, 2020), and our findings suggest that one factor contributing to this might be disrupted prethalamic axonal growth.…”

Rapid and robust directed differentiation of mouse epiblast stem cells into definitive endoderm and forebrain organoids

“…Within cells in this cluster, there was further heterogeneity based on the relative expression levels of Ptprd and Pax6, which distinguishes the lateral or the medial portions of the developing prethalamus in vivo (Guo and Li, 2019;Kim et al, 2020;Li et al, 2020;Sommer et al, 1997;Tuttle et al, 1999). In addition, more mature prethalamic neurons express higher levels of L1cam and Nrcam, which play a role in the pathfinding of axons from prethalamic neurons that project into the thalamus (Molnar et al, 2012;Quintana-Urzainqui et al, 2020) (Fig. S6B).…”