The Role of Sonic Hedgehog of Neural Origin in Thalamic Differentiation in the Mouse

Abstract

The specification of the intricate neuronal assemblies that characterize the forebrain is not well understood. The ventral spinal cord is specified through a concentration gradient of Sonic hedgehog (Shh) protein secreted by the notochord. Shh is expressed also in the forebrain neuroepithelium (neural Shh) and the underlying notochord and prechordal plate. Neural Shh is essential for the development of the prethalamus (ventral thalamus), but its effects on the thalamus (dorsal thalamus) are still unclear. We hypothesized that neural Shh would act on a previously regionalized dorsal diencephalic region to promote the emergence of specific thalamic nuclear and histological traits. To find out, we generated a conditional mouse mutant line specifically lacking Shh expression in the diencephalic neuroepithelium. We show that the transcription factor Gbx2, required for thalamic development downstream Shh, is expressed in our mutant in a restricted thalamic region and is necessary and sufficient for the differentiation of the medial and intralaminar thalamic nuclei. In the rest of the thalamus, neural Shh is required to promote neuronal aggregation into nuclei as well as axonal extension. In this way, the individual thalamic nuclei show differential dependence on Shh, Gbx2, or both for their differentiation. Additionally, Gbx2 is required for the survival of thalamic neurons.

Spatial and temporal requirements for sonic hedgehog in the regulation of thalamic interneuron identity

“…Thus, the apparent pTH-R to pTH-C fate switch observed in Shh SBE1/-mutants at E12.5 was partially reverted by E16.5. Recent studies demonstrated that embryos lacking Shh (or the ability to respond to Shh) from both the diencephalic ventral midline and zli showed a more profound thalamic phenotype, including the complete loss of pTH-R and rostral pTH-C neuronal derivatives (Vue et al, 2009;Szabó et al, 2009). Therefore, in Shh SBE1/-embryos, it is conceivable that the exposure of mis-specified pTH-R neurons to the zli source of Shh during their migration to the vLG resulted in their partial recovery.…”

“…Shh is also expressed in a dorsally projecting spike, the zona limitans intrathalamica (zli), that forms at the p2-p3 boundary. The exposure of the thalamus to two Shh signaling centers has made it difficult to reconcile the specific roles of either one in regional patterning and/or neuronal fate specification (Hashimoto-Torii et al, 2003;Kiecker and Lumsden, 2004;Vieira et al, 2005;Szabó et al, 2009;Vue et al, 2009). …”

“…Early sources of Shh from the prechordal plate and/or ventral midline are required for the proliferation and survival of diencephalic precursors, whereas at later stages, a gradient of Shh signaling from the ventral midline and/or zli promotes thalamic regionalization, neuronal progenitor identity and nucleogenesis (Ishibashi and McMahon, 2002;Hashimoto-Torii et al, 2003;Kiecker and Lumsden, 2004;Vieira et al, 2005;Szabó et al, 2009;Vue et al, 2009). Conditional mouse mutants that either block the production of, or the response to, Shh throughout the thalamic primordium show a profound deficit in pTH-R and rostral pTH-C progenitor identities and their postmitotic derivatives (Szabó et al, 2009;Vue et al, 2009).…”

Role of NeuroepithelialSonic hedgehogin Hypothalamic Patterning

“…In the diencephalic neuroepithelium, Shh shows an intriguing and dynamic pattern of expression with domains in the caudal-dorsal diencephalon [zona limitans interthalamica (ZLI)] and the rostral-ventral diencephalon (hypothalamic domain), which seem strategically situated to influence the formation of the DTJ. In the caudal diencephalon, neural Shh from the ZLI specifies the prethalamus (PTh) (Hashimoto-Torii et al, 2003;Kiecker and Lumsden, 2004;Vieira et al, 2005;Hirata et al, 2006;Scholpp et al, 2006;Guinazu et al, 2007) and promotes growth and differentiation of specific subdivisions of the thalamus (Szabó et al, 2009). The role of neural Shh in the rostral diencephalon (hypothalamus) and DTJ, however, is only starting to be analyzed.…”

The Development of the Thalamic Motor Learning Area Is Regulated by Fgf8 Expression

“…The zona limitans intrathalamica (ZLI) is a central boundary between the prethalamus and the thalamus that expresses sonic hedgehog (Shh), regulating both ventrodorsal and anteroposterior regionalization of the diencephalic neuroepithelium (Larsen et al, 2001;Kiecker and Lumsden, 2004;Zeltser, 2005;Scholpp et al, 2006;Vieira and Martinez, 2006;Szabó et al, 2009;Vue et al, 2009). In addition to Shh, other morphogenetic signals provided by the roof plate mediate patterning activity in the diencephalon, including Wnts (Yamaguchi, 2001;Braun et al, 2003;Zhou et al, 2004;Lavado et al, 2008) and Bmps (Furuta et al, 1997;Lim et al, 2005).…”