Hedgehog Controls Limb Development by Regulating the Activities of Distinct Transcriptional Activator and Repressor Forms of Cubitus interruptus

Abstract

Hedgehog (Hh) proteins play diverse organizing roles in development by regulating gene expression in responding cells. The Gli homolog Cubitus interruptus (Ci) is involved in controlling the transcription of Hh target genes. A repressor form of Ci arises in the absence of Hh signaling by proteolytic cleavage of intact Ci. We show that this cleavage is essential for limb patterning and is regulated by Hh in vivo. We provide evidence for the existence of a distinct activator form of Ci, which does not arise by mere prevention of Ci proteolysis, but rather depends on a separate regulatory step subject to Hh control. These different activities of Ci regulate overlapping but distinct subsets of Hh target genes. Thus, limb development is organized by the integration of different transcriptional outputs of Hh signaling.

Indian hedgehog: Its roles and regulation in endochondral bone development

“…Zou et al [1997] first reported that overexpressing a constitutively active mutant of BMP type IA receptor induced PTHrP expression in the periarticular perichondrium. Based on these data and studies in many different species showing that BMPs are one of the major targets of Hh signaling [Methot and Basler, 1999], it was proposed that BMPs expressed in the perichondrium can act downstream of Ihh. Indeed, ectopic Ihh expression in chicken embryos induced BMPs 2 and 4 in the perichondrium [Pathi et al, 1999], and BMP activation of BMP receptors in the periarticular perichondrium can increase PTHrP expression.…”

Regulation of Hedgehog signaling: a complex story

“…Hh is required to convert the default Ci 155 to a functional transcriptional activator, as evidenced by clones of cells expressing a non-cleavable form of Ci [65]. These cells accumulate full-length Ci 155 , but do not activate target genes in the absence of Hh stimulation.…”

“…The loss of epitope recognition of Ci by the 2A1 antibody, and its relationship to Ci*, are not presently understood. However, it is clear that Ci* is a distinct Ci species, as clones of cells at the A/P boundary that do not express Ci do not activate anterior en [65].…”

Opposing inputs by Hedgehog and Brinker define a stripe ofhairyexpression in theDrosophilaleg imaginal disc

“…These genes are each expressed in a stripe along the AP compartment boundary, but curiously, stripe widths among the genes varies as does register relative to the AP boundary. This has been explained in terms of differential response of Hhtarget genes to the repressor and activator forms of Ci (Ci-R and Ci-A, respectively) found in anterior compartment cells (Methot and Basler, 1999;Muller and Basler, 2000;Wang and Holmgren, 1999). ptc, for example, has been proposed to respond only to the maximal levels of Ci-A found in cells nearest the AP boundary, while dpp responds to lower levels of Ci-A and also to Ci-R.…”

“…Ci is expressed specifically in anterior compartment cells and exists in either a cleaved repressor or a full-length activator form (Aza-Blanc et al, 1997). In cells near the AP boundary, Hh prevents cleavage and promotes nuclear entry of the full-length form of Ci, allowing activation of Hh-target genes, such as dpp (Aza-Blanc et al, 1997;Chen et al, 1999;Methot and Basler, 1999;Methot and Basler, 2000;Wang and Holmgren, 1999;Wang and Holmgren, 2000).…”