The role of primary cilia in Shh signaling. (a) In the absence of Shh, its receptor Ptch1 localizes to primary cilia and prevents Smo from entering primary cilia. Gli3 is constitutively proteolytically cleaved to a Gli3 repressor (Gli3R) to repress Shh target genes. When Shh binds to Ptch1, Ptch1 disappears from the cilia allowing Smo to enter primary cilia, where it activates Gli2 to become transcriptional activator (Gli2A) and inhibits Gli3R formation, leading to Shh target gene expression. (b) In the absence of cilia, neither Gli2A nor Gli3R form.

The role of primary cilia in medulloblastoma formation. (a–d) SmoM2 is insensitive to Ptch1 inhibition and constitutively localizes to primary cilia, where it induces Gli2A formation and inhibits Gli3R formation (a), leading to medulloblastoma development (c). Without primary cilia in hGFAP::Cre; SmoM2^fl/+; Kif3a^fl/fl mutants, SmoM2 as well as normal Shh signaling cannot activate downstream signaling (b), resulting in hypomorphic cerebellum (d). (e,g) hGFAP::Cre; CLEG2^fl/+ mutants express Gli2ΔN, which constitutively activates Shh target genes independent of Shh signaling or primary cilia (e), but alone does not induce medulloblastoma (g). The presence of Gli3R may counteract oncogenic activity of Gli2ΔN (e). (f, h) Gli2ΔN, without cilia in hGFAP::Cre; CLEG2^fl/+; Kif3a^fl/fl mutants, induce medulloblastoma (h). Without cilia, Gli3R does not form, which might allow Gli2ΔN to induce medulloblastoma formation (f). Scale bar = 100 µm.

The role of primary cilia in brain development. (a–d) Ift88^cbs/cbs mutants show defects in the formation of dorsomedial telencephalic structures (b) and of telenecephalic-diencephalic boundaries (d). Arrows in (b) and (d) indicate heterotopias in the mutants. Ift88^cbs/cbs mutants have primary cilia, but Shh signaling within the cilium including the formation of Gli3R (see text) is probably disrupted. (e,f) At P10, control DG have many radial astrocytes (arrow, brown staining by an anti-GFAP antibody) that function as adult neural stem cells in the DG, whereas hGFAP::Cre; Kif3a^fl/fl mutants lacking primary cilia in GNPs fail to establish radial astrocytes. (g,h) At P1, control cerebellum has a thick external granule layer (arrow) containing many CGNPs, whereas hGFAP::Cre; Kif3a^fl/fl mutants lacking primary cilia in CGNPs have a small cerebellum with thin external granule layer containing a few CGNPs. (a) – (d) are reproduced from Willaredt et al with permission. Scale bar = 300 µm (a–d) and 100 µm (e–h).