Hedgehog signaling from the ZLI regulates diencephalic regional identity

Abstract

The zona limitans intrathalamica (ZLI), a narrow compartment in the vertebrate forebrain that bisects the diencephalon transversely, expresses the secreted factor sonic hedgehog (Shh). Because genetic disruption of Shh in mouse causes severe early developmental defects, this strategy has not been useful in identifying a ZLI-specific role for this gene. To modulate Shh signaling in a spatiotemporally restricted manner, we carried out gain- and loss-of-function experiments in chick embryos using in ovo electroporation and found that Shh signaling is required for region-specific gene expression in thalamus and prethalamus, the major diencephalic brain areas flanking the ZLI. We further show that differential competence of thalamic and prethalamic primordia in responding to Shh signaling is regulated by the transcription factor Irx3. We show that, through the release of Shh, the ZLI functions as a local signaling center that regulates the acquisition of identity for these important diencephalic regions.

Role of NeuroepithelialSonic hedgehogin Hypothalamic Patterning

“…1V ). In the ZLI domain, maintenance of activity in the Shh locus requires Shh (feedback loop) (Kiecker and Lumsden, 2004;Zeltser, 2005), which explains the lack of a ZLI in this mutant, and possibly also the lack of a bp domain. In contrast, the suboptical domain and the MAM domain can activate Shh expression independently of Shh of neural origin.…”

“…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 Basics of Brain Development

“…The patterning that emerges in the embryonic period provides only a primitive map of eventual nervous system organization, but it sets the stage for later developments. Embryonic patterning affects all brain regions from the forebrain through the spinal column, such that by the end of the embryonic period in GW8 primitive patterning of sensorimotor regions within the neocortex is established (Bishop et al 2002), major compartments within diencephalic and midbrain regions have differentiated (Nakamura et al 2005;Kiecker and Lumsden 2004), and the segmental organization of the hindbrain and spinal column have been specified (Lumsden and Keynes 1989;Gavalas et al 2003). Space does not permit an extended discussion of embryonic neural patterning.…”

Molecular Pathways Controlling Development of Thalamus and Hypothalamus: From Neural Specification to Circuit Formation

“…Experimental abrogation of Shh signaling in zebrafish, chick, and mouse results in loss of genetic fate determinants and cell identity in prethalamus and thalamus (Kiecker and Lumsden, 2004;Scholpp et al, 2006;Vue et al, 2009). Furthermore, ectopic activation of the Shh pathway by misexpression of a constitutively active Shh effector mutant (SmoM2) induces the expression of thalamic markers such as Gbx2, Ngn2, Olig2, and Olig3 in the mouse pretectum (Vue et al, 2009).…”