Gli3 Conditional Knockout mouse models

Functioning chiefly as a repressor, Gli3 is the mouse ortholog of human GLI3 and encodes a zinc finger protein that, in the absence of Hedgehog ligand, undergoes PKA-primed, GSK3 and CK1 mediated phosphorylation followed by limited proteasomal processing into a truncated Gli3R that occupies target promoters and silences them, a step requiring intact ciliary trafficking through Kif7 and restraint by Sufu. Human GLI3 lesions produce Greig cephalopolysyndactyly and, with specific mid-protein truncations, Pallister-Hall syndrome, while the classic mouse extra-toes allele causes preaxial polydactyly and perinatal lethality in homozygotes, so conditional deletion is preferable for limb, neural tube, and craniofacial work beyond birth. A repressor-only knockin that constitutively yields Gli3R distinguishes loss of repression from loss of activator capacity, and patient-matched frameshift knockins model Pallister-Hall directly. Gli2 supplies activator output that shapes the Gli3 phenotype, so compound genetics and precise driver selection determine interpretability.

Tissue restricted knockout of Gli3 keeps wild type function everywhere else. Breeding is often more robust, and the setup mirrors patient biology where mutations arise in a subset of cells.