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Review
. 2012 May;35(10):1573-85.
doi: 10.1111/j.1460-9568.2012.08119.x.

Mechanisms controlling the guidance of thalamocortical axons through the embryonic forebrain

Zoltán Molnár  1 , Sonia Garel, Guillermina López-Bendito, Patricia Maness, David J Price
Affiliations
Review

Mechanisms controlling the guidance of thalamocortical axons through the embryonic forebrain

Zoltán Molnár et al. Eur J Neurosci. 2012 May.

Abstract

Thalamocortical axons must cross a complex cellular terrain through the developing forebrain, and this terrain has to be understood for us to learn how thalamocortical axons reach their destinations. Selective fasciculation, guidepost cells and various diencephalic and telencephalic gradients have been implicated in thalamocortical guidance. As our understanding of the relevant forebrain patterns has increased, so has our knowledge of the guidance mechanisms. Our aim here is to review recent observations of cellular and molecular mechanisms related to: the growth of thalamofugal projections to the ventral telencephalon, thalamic axon avoidance of the hypothalamus and extension into the telencephalon to form the internal capsule, the crossing of the pallial-subpallial boundary, and the growth towards the cerebral cortex. We shall review current theories for the explanation of the maintenance and alteration of topographic order in the thalamocortical projections to the cortex. It is now increasingly clear that several mechanisms are involved at different stages of thalamocortical development, and each contributes substantially to the eventual outcome. Revealing the molecular and cellular mechanisms can help to link specific genes to details of actual developmental mechanisms.

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Figures

Figure 1
Figure 1
The anatomy of the developing forebrain and the location of prethalamic cell groups providing guidance for thalamocortical axons in embryonic mouse brain. (A) A sagittal view of the brain around E10.5 showing the pretectal, thalamic and prethalamic anlagen. (B) By E12.5 the telencephalic vesicles expand over the diencephalon; note that the prethalamus (PT) lies anterior to the thalamus (T). These two structures are separated by the zona limitans intrathalamica (ZLI). (C) The appearance of the forebrain when cut as shown by the red line in B at E14 (D) Thalamocortical axons grow from the thalamus, through the prethalamus and into the telencephalon. The prethalamus contains cells that express the markers Pax6 and RPTPδ (Tuttle et al., 1999). (E) An example of a section stained with an antibody for the Pax6 transcription factor (E14). The positions of prethalamic groups of cells proposed by Tuttle et al. (1999) to project to the thalamus and provide guidance to thalamocortical axons are shown. These groups were originally called VTh1 and VTh2, with VTh1 split into a dorsal and a ventral domain. The dorsal domain of VTh1 expresses a low level of Pax6, whereas the ventral domain of VTh1 expresses a high level of Pax6. (F) VTh2 does not express Pax6 but does express RPTPδ.
Figure 2
Figure 2
The position of various cell populations guide thalamic axons. A and B depict the various subdivisions in the diencephalon (ET - epithalamus, T-thalamus, PT-prethalamus, TE-thalamic eminence, HT-hypothalamus) and telencephalon (MGE-medial ganglionic eminence, GP-globus pallidus, LGE-lateral ganglionic eminence, PSPB-pallial subpallial boundary, VP-ventral pallium or SP-subpallium, CTX-cerebral cortex, Str-striatum) and their bounadary (DTB-diencephalic and telencephalic boundary). C and D issultrates the early connectivity in the telencephalon and diencephalon. Prethalamic (PTh-Th) and ventral telencephalic (internal capsule, VThel-Th) cells with thalamic projections (purple and yellow respectively) are instrumental in the early thalamic axon guidance. Panel in C illustrates the migration of the corridor cells and their interactions with the thalamocortical projections. Corridor cells (light blue) originate from the lateral ganglionic eminence (LGE) at embryonic day 12 (E12) and migrate tangentially toward the diencephalon, where they form a permissive “corridor” for the thalamic projections (red) to navigate them through the internal capsule. Modified based on López-Bendito and Molnár (2003) and Hanashima et al., (2006).
Figure 3
Figure 3
Evidence that Pax6 plays a role in corridor formation. (A) Normally, Pax6-expressing cells (purple) are located ventral to the corridor/ developing internal capsule in the medial ganglionic eminence (MGE); those located laterally comprise the lateral cortical stream migrating from the pallial-subpallial border (arrow). Islet1-expressing cells (green) migrate from the progenitor layer of the lateral ganglionic eminence (LGE; arrow) to form the corridor through which thalamocortical axons grow (arrow). (B) In conditional mutant embryos with selective reduction of Pax6 in specifically the ventral telencephalon but neither thalamus not cortex, there are fewer Pax6-expressing cells ventral to the corridor than normal (other populations of Pax6-expressing cells outside the region of Pax6 deletion are not shown since they are not affected). Cells from the lateral ganglionic eminence migrate to form a corridor that is abnormally broad with a lower peak density of Islet1-expressing cells; many Islet1-expressing cells stray into the area depleted of Pax6 expression. Many thalamic axons fail to enter this abnormal corridor or exit it along its length. Data are taken from Simpson et al. (2009).
Figure 4
Figure 4
Scheme of thalamocortical axon trajectories from thalamic nuclei through the subpallium/ventral telencephalon to arrive to distinct neocortical areas. Upper right panles: Schematic diagram illustrating multiple carbocyanine dye placements in the cerebral cortex positioned along an anterioposterior axis revealed the arrangements of backfilled dorsal thalamic neurons in a mediolateral fashion. The schematic panels indicate the appropriate sections with labelling. The right hemisphere is enlarged to illustrate some of the moleculas mechanisms that are involved in the guidance fo the thalamic axons across the thalamic eminence, corridor and subpallium to reach the appropriate regions in the cortex. TCAs from different nuclei in the thalamus (VA/VL: ventroanterior/ventrolateral nuclei, VB: ventrobasal complex, dLGN: dorsal lateral geniculate nucleus), emerge at the thalamic eminence en route to the neocortex, and are sorted within a corridor of Islet1-positive cells in the subpallium/ventral telencephalon along the rostral to caudal axis (E13.5-E15.5 in the mouse). Within the corridor, TCAs expressing different combinations of axon guidance cue receptors (listed in the box within the dorsal thalamus) are guided by gradients of repellent and attractant cues (EphrinA5, Netrin1, Semaphorin3A, 3F, Slit1), influenced by Neuregulin-1 and serotonin (5-HT, 5-hydroxy tryptamine). In the ventral pallium, with the exception of Slit1, similar gradients are present. The thalamic axons target cortical areas that will contribute putative primary motor cortex (M1), somatosensory cortex (S1), and visual cortex (V1), but their entry to the cortex is regulated by subplate. The some of the various grandients in subplate and cortical plate are listed (Fgf8, Sp8, COUPTF1, Pax6, Emx2). Within the neocortex additional molecular cues and activity- dependent mechanisms promote the final synaptic targeting of TCAs. This simple initial topography can be considerably rearranged at the time of entry to the cortical plate.
Figure 5
Figure 5
A summary of recent experiments testing the importance of corticofugal axons for thalamic axonal crossing of the PSPB carried out by Chen et al. (2012). (A) Normally, axons from the thalamus (T; red) cross the PSPB in close association with descending axons from the cortex (green). (B) In conditional Emx1Cre; APCloxP/loxP mutants, the development of cortical neurons and hence of corticofugal axons is blocked but, although the thalamus and ventral telencephalon are unaffected, thalamic axons do not cross the PSPB. (C) Culture experiments showed that both normal cortex and mutant cortex stimulate the growth of axons from the thalamus by equal amounts. This suggests that the inability of thalamic axons to cross the PSPB in Emx1Cre; APCloxP/loxP mutants is unlikely to be explained by long-range chemorepulsion by mutant cortex. (D) When normal cortex was substituted for mutant cortex in slice cultures from the brains of Emx1Cre; APCloxP/loxP embryos, corticofugal axons were restored and thalamic axons were able to cross the PSPB. These results provide evidence for the importance of corticofugal axons in allowing thalamic axons to cross the PSPB.
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