Gli proteins and the control of spinal-cord patterning

Abstract

The secreted protein sonic hedgehog (Shh) is crucial for the specification of neuronal subtype identity in the vertebrate neural tube. Zinc-finger proteins of the Gli family are known to be transcriptional mediators of Shh signalling, and to coordinately pattern the dorsal-ventral axis of the spinal cord. Recent studies indicate that additional signals may provide positional information in parallel to Shh to specify neuronal fate in this tissue. We review the role of Gli proteins in spinal-cord development and propose that various upstream patterning signals may be integrated by the Gli proteins to direct a coherent programme of neurogenesis.

Figure 1

Ventral neural progenitor domains of the spinal cord are defined by sonic-hedgehog-regulated combinatorial expression of transcription factors. (A) Five distinct ventral neuronal subtypes arise from an equivalent number of progenitor domains in the ventricular zone of the ventral spinal cord. Progressively more dorsal progenitor domains are exposed to a decreasing concentration of sonic hedgehog (Shh) protein. (B) The concentration gradient of Shh regulates the ventral expression domains of a series of transcription factors in ventral progenitor (p) cells. Three aspects are crucial to this system: Shh either represses (class I genes) or induces (class II genes) expression at different concentration thresholds (left). Progenitor gene-expression domains are refined and maintained by negative cross-regulatory interactions between those proteins that share a boundary (centre). The combinatorial expression of homeodomain proteins in distinct progenitor domains determines the neuronal subtype that arises from each domain (right). D, dorsal; Dbx, developing brain homeobox transcription factor; FP, floor plate; Irx, iroquois homeodomain protein; MN, motor neuron; N, notochord; Nkx, Nkx homeodomain protein; Pax, Paired homeodomain protein; V, ventral; V0–V3, ventral interneurons 0–3.

Figure 2

Dorsoventral spinal-cord patterning defects in Gli mutant embryos can be explained by a gradient model of Gli activator and repressor activity. (A) Effects of sonic hedgehog (Shh) and Gli loss-of-function mutations on patterning of the ventral and intermediate regions of the spinal cord. In Gli2^−/− embryos, the most ventral cell types—the floorplate (FP) and ventral interneuron 3 (V3) neurons—are absent and there is a concomitant expansion of the motor neuron (MN) domain. By contrast, in Gli3^−/− mutants, patterning of the intermediate region of the neural tube is disrupted (see text for details). In comparison with Shh-null mutants, embryos that lack both Shh and Gli3 function have substantially restored dorsoventral patterning. Inhibition of all Gli activity by the misexpression of the dominant-negative protein Gli3R completely suppresses the formation of all ventral and intermediate neuronal subtypes. (B) According to the model, Shh-induced, graded Gli activator and repressor transcriptional activities assign distinct cellular identities along the ventral neural tube. The ventral-to-dorsal gradient of Shh activity induces a parallel gradient of Gli activator function, that is, a gradient that is maximal in the ventral midline and declines in dorsal regions of the neural tube. The gradient of Gli repressor activity is orientated in the opposite direction to the Shh gradient because of the antagonistic effect of Shh signalling on Gli repressor activity. The model proposes partial redundancy of the transcriptional activity of each Gli protein by the other so that, for example, in the absence of Gli2, the transcriptional activation function of Gli3 partially compensates for this. The combined transcriptional activity of the Gli proteins results in a gradient of transcriptional activation (+) in ventral regions of the neural tube and repression (−) in intermediate and dorsal regions. dI, dorsal interneuron; WT, wild type.