Sonic hedgehog functions through dynamic changes in temporal competence in the developing forebrain

Abstract

Morphogens act during development to provide graded spatial information that controls patterning and cell lineage specification in the nervous system. The role of morphogen signaling in instructing the expression of downstream effector transcription factors has been well established. However, a key requirement for morphogen signaling is the existence of functional intracellular machinery able to mediate the appropriate response in target cells. Here we suggest that dynamic changes in the temporal responses to Shh in the developing ventral telencephalon occur through alterations in progenitor competence. We suggest these developmental changes in competence are mediated by a transcriptional mechanism that intrinsically integrates information from the distinct signaling pathways that act to pattern the telencephalic neuroepithelium.

Figure 1. Developmental changes in the expression of Shh in the developing ventral telencephalon

(top panel) Sources of Shh (red) in the mesendoderm induce expression of Shh in the most ventral aspect of the telencephalon (Tel), as observed in coronal sections of E9.5 embryos. (bottom panel) As development progresses, the expression of Shh becomes progressively confined to restricted regions of the ventral telencephalon. By E12.5 it can be detected at rostral levels in the preoptic area (POA) and the mantle of the medial ganglionic eminence (MGE). Shh expression is also observed at this age in the amygdala region of the caudal ganglionic eminence (CGE). Ctx, Cortex; Di, Diencephalon; Hind, Hindbrain; Mid, Midbrain.

Figure 2. Early telencephalic development is characterized by the dynamic expression of distinct homeobox transcription factors that reflect the sequential appearance of the ventral eminences

(A) At E9.5, Nkx2-1 expression appears within a ventral domain that is induced to express Shh. These events define the first temporal competence window (C1). This event defines the MGE at the molecular level and expression of Nkx2-1 persists in this region throughout development. Around E10.0 the second competence window is initiated (C2), during which the expression of Gsx2 accompanies the emergence of the more dorsally positioned lateral domain that will give rise to the LGE. (B) After E10.0, ventral patterning is already established and Shh activity is predominantly required for proliferative control of progenitors. A horizontal view of the ventral ganglionic eminences reveals a repeated pattern in both C1 and C2-derived structures where the ventral aspect of each region gives rise to early-born projection neurons (light colors) while the more lateral/dorsal domains mainly generate later-born interneurons (darker colors).

Figure 3. The differential expression of members of the Gli/Ci family of transcription factors controls the response of progenitors to Shh in the ventral telencephalon at distinct embryonic ages

(top panel) The distribution of Gli protein expression within the telencephalon at E9.5 [72] and (middle and bottom panels) E12.5 in patterns dictates the differential responses of progenitors to Shh. At E12.5, the targets of Shh-signaling Nkx6-2 (blue) and Gli1 (green) can be observed only in the Gli2-expressing domains (purple) that are closest to the ventral sources of Shh (red) along the rostro-caudal axis of the telencephalon. Gli3 (brown) is expressed in a dorsal-to-ventral gradient in the entire telencephalon with a characteristic low level of expression in the MGE (that is apparently insufficient to provide enough Gli-activator function to allow for expression of Nkx6-2 or Gli1).

Figure 4. Key genetic interactions involving Shh signaling that pattern and determine the fate of ventral telencephalic progenitors during C1 and C2 temporal competence windows

During C1, Shh is indirectly required to establish the ventral expression of Nkx2-1 in the MGE anlage through a derepression of FGF signaling. At later stages, gene expression reveals that mostly positive Shh-signaling mediated through Gli proteins is associated with LGE/CGE development. It is at present unclear whether FGF-signaling plays a role during C2 inductive events.