Early thalamocortical tract guidance and topographic sorting of thalamic projections requires LIM-homeodomain gene Lhx2

Abstract

The thalamocortical tract is the primary source of sensory information to the cerebral cortex, but the mechanisms regulating its pathfinding are not completely understood. LIM-homeodomain (LIM-HD) gene Lhx2 has been proposed to participate in a combinatorial "code" to regulate dorsal thalamic patterning and also the topography of thalamocortical projections. Here, we report that Lhx2-/- embryos exhibit a gross disruption in the early development of the thalamocortical tract, such that thalamic axons are unable to enter the ventral telencephalon. A possible cause for this deficit is a severe reduction of "pioneer" cells in the mutant ventral telencephalon that constitutes a putative mechanism for guiding the entry of the thalamocortical tract into this structure in vivo. However, in vitro, the thalamocortical tract is able to enter the ventral telencephalon, and this permitted an examination of whether thalamocortical topography is normal in the Lhx2 mutant. Contrary to hypotheses that proposed a cell-autonomous role for Lhx2 in the thalamus, Lhx2-/- thalamic explants generate a normal topography of projections in control ventral telencephalic preparations. This is consistent with our findings of normal patterning of the Lhx2 mutant dorsal thalamus using a wide array of markers. In the reverse experiment, however, control thalamic explants display aberrant topography in Lhx2-/- telencephalic preparations. This perturbation is restricted to projections from caudal thalamic explants, while rostral and middle explants project normally. Thus Lhx2 is required for multiple steps in thalamocortical tract pathfinding, but these functions appear localized in the ventral telencephalon rather than in the dorsal thalamic neurons. Furthermore, the absence of Lhx2 in the ventral telencephalon selectively disrupts a subset of thalamic axon topography, indicating a specific rather than a general perturbation of cues in this structure.

TheGli3Hypomorphic MutationPdnCauses Selective Impairment in the Growth, Patterning, and Axon Guidance Capability of the Lateral Ganglionic Eminence

“…Alternatively, the dorsal shift of the PSPB might interfere with the projection of these neurons as they might be separated from attractive guidance cues emanating from the cortex (Ló pez-Bendito et al, 2006). Given the known role of pioneer neurons in the development of forebrain axonal connections (McConnell et al, 1989;De Carlos and O'Leary, 1992;Supèr et al, 1998;Lakhina et al, 2007;Piper et al, 2009), defective LGE pioneer development in Pdn/Pdn embryos provides a strong explanation for the delay of CTAs to cross the PSPB. In addition, the defective formation of the PSPB might provide an alternative, not mutually exclusive, explanation for the navigation defects of CTAs (Molnár and Blakemore, 1995a;Molnár and Butler, 2002).…”

TheLhx2Transcription Factor Controls Thalamocortical Axonal Guidance by Specific Regulation of Robo1 and Robo2 Receptors

“…Tamoxifen administration generated Gbx2Cre ER/ϩ : Lhx2 flox/flox (thalamic deletion of Lhx2; named Th-Lhx2) conditional knock-out mice, carrying a recombinant Lhx2 locus in the Creexpressing cells, and lacking functional Lhx2 in the diencephalic thalamic neuroepithelium (see Results). Lhx2-null mutant embryos (Lhx2 Ϫ/ Ϫ ) (Porter et al, 1997;Lakhina et al, 2007) were provided by Shubha Tole (Tata Institute of Fundamental Research, Mumbai, India). Lhx2 Ϫ/ Ϫ embryos die in utero by embryonic day 15.5 (E15.5), limiting the ages that could be analyzed.…”

“…Lhx2 mRNA is expressed in the thalamus from the onset of thalamic neurogenesis (Nakagawa and O'Leary, 2001;Lakhina et al, 2007). In Lhx2-null mice, severe defects in thalamocortical axon guidance have developed by E14.5 (Lakhina et al, 2007).…”

“…In Lhx2-null mice, severe defects in thalamocortical axon guidance have developed by E14.5 (Lakhina et al, 2007). However, it remains unclear whether Lhx2 exerts this effect in a cellautonomous manner and, moreover, whether it selectively regulates axon guidance in distinct subsets of thalamic neurons in vivo.…”

“…The Lhx2 transcription factor is a member of the LIM-HD family of proteins, and it is strongly expressed in the thalamus during development (Rétaux et al, 1999;Nakagawa and O'Leary, 2001). Severe thalamocortical pathfinding defects have been described in Lhx2-null mice (Lakhina et al, 2007), implicating this transcription factor in the guidance of these axons. As Lhx2 is also expressed in other forebrain areas, it is essential to restrict the loss of Lhx2 to thalamic neurons to precisely determine the role of this transcription factor in thalamocortical development.…”