Balanced Shh signaling is required for proper formation and maintenance of dorsal telencephalic midline structures

Viral over-expression of Shh in the embryonic telencephalon prevents formation of the cortical hem and choroid plexus, while expanding the roof plate. In a transgenic model where cholesterol-lacking ShhN is expressed from one allele (ShhN/+), genes expressed in all three domains, cortical hem, choroid plexus and roof plate expand. In Gli1/2 -/- mutant brains, where Shh signaling is reduced, the roof plate expands, again at the expense of cortical hem and plexus. Cell autonomous activation of Shh signaling in the dorsal midline through Gdf7-driven activated Smoothened expression results in expansion of the Wnt3a-expressing cortical hem into the plexus domain. In addition, developmental stage determines dorsal midline responsiveness to Shh.Together, these data demonstrate that balanced Shh signaling is critical for maintaining regional boundaries within the dorsal midline telencephalic organizing center.The telencephalic dorsal midline contains two organizing centers: the roof plate and cortical hem [1,2]. The roof plate is initially induced by signals from the overlying epidermal ectoderm, and once established, provides a secondary source of secreted TGFβ-family members along the entire dorsal midline of the developing neural tube [3]. Fate-mapping experiments show that the roof plate is derived from Wnt1-expressing cells in the overlying neuroectoderm, and develops from lineage-restricted cellular compartments [4]. Evidence that the roof plate may be an organizer stems from genetic ablation experiments demonstrating roof plate-dependent dorsal interneuron specification in the spinal cord, and cortical and choroid plexus development in the telencephalon [5-7]. In addition, it has been shown that the roof plate directs choroid plexus formation through a cell non-autonomous mechanism [5]. The cortical hem, originally identified as an embryonic structure marked by Wnt expression [8], exhibits hippocampal organizer activity [9]. Targeted inactivation of Wnt3a and the sig