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. 2024 Mar 22;10(12):eadn4649. doi: 10.1126/sciadv.adn4649

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Fig. 1. — (A) Schematic of aberrant mechanisms of SHH signaling in cerebellar GCPs in MB development (left). In Ptch1-mutant Ptf1a^Cre/+;Ptch1^fl/fl MB, by deletion of Ptch1 encoding a receptor for SHH, SMO signaling is disinhibited and highly activated, leading to the generation of activated GLI (GLI^A). In Smo-mutant MASTR-SmoM2 or Atoh1-CreER^T2;Rosa26^LSL-SmoM2 MB, oncogenic constitutively activated form of SMO results in GLI activation and aberrant SHH signaling. (B) Schematic of cerebellar tumor development in Ptch1- (top) and SmoM2-mutant (bottom) MB. Red arrowheads mark conditionally gene-targeted cell populations. PNLs (purple) lead to MB development. E, embryonic day; P, postnatal day. (C) Representative photographs of dissected brains of Ptf1a^Cre/+;Ptch1^fl/fl (bottom left) mice that develop MBs marked by white arrows and dashed circles, as compared to Ptf1a^Cre/+;Ptch1^fl/wt mice (top left) that do not develop tumors. Immunofluorescence microscopy (right) shows high Ki67 (green) and low NeuN (red) expression in MB tumors, with nuclei marked with DAPI (blue). The edge of the tumor (white inset) is magnified with NeuN-positive cells on tumor edge corresponding to normal cerebellum. (D) Survival of Ptf1a^Cre/+;Ptch1^fl/fl;Pgbd5^+/+ (black) and Ptf1a^Cre/+;Ptch1^fl/fl;Pgbd5^−/− (red) mice. (E) Survival of Ptf1a^Cre/+;Ptch1^fl/fl mice with conditional knockout (CKO) of Pgbd5^fl/− (blue) or control Pgbd5^+/− (black) or Pgbd5^−/− (red) littermates. (F) Genomic PCR analysis of conditional Pgbd5 excision in Pgbd5^fl/− CKO Ptch1-mutant tumors demonstrates that seven of nine (79%) analyzed tumors retain intact Pgbd5, as detailed in fig. S1D. (G) Survival of MASTR-SmoM2 mice with CKO of Pgbd5^fl/fl (red), as compared to control Pgbd5^+/+ (black) or Pgbd5^fl/+ (blue) littermates. (H) Genomic PCR analysis of conditional Pgbd5 excision in MASTR-SmoM2; Pgbd5^fl/fl tumors demonstrates that four of five (80%) analyzed tumors retain Pgbd5 floxed alleles, as detailed in fig. S2B.