Table 3.
Current mouse models to study the function of Ift-B proteins in bone development
| Gene | Mouse models | Mutation | Cilia | Phenotype | Pathways | Ref |
|---|---|---|---|---|---|---|
| Ift80 | Ift80gt/gt | Gene trap, hypomorph with low level wild-type transcript production | Normal cilia | Usually die perinatally. Severe growth retardation with short long bones, narrow ribcage and polydactyly |
Less Hh activity. | (70) |
| Ift88 | Ift88Tg737Rpw (ORPK) | Transgene insertion-induced hypomorphic allele | Stunted and malformed cilia | Survive to young adulthood. Scruffy fur, severe growth retardation, cystic renal phenotype, preaxial polydactyly, defects in skeletal patterning and growth with craniofacial abnormalities, cleft palate, unfused tibia and fibula, and significantly smaller growth plates. |
Defects in PDGFR-α/PDGF-A signaling. | (168–171) |
| Ift88Δ2–3βGal (Ift88tm1Rpw) | A Null mutation | Cilia loss | Arrested at mid-gestation with neural tube defects, enlargement of the pericardial sac and left-right asymmetry defects. | Reduced expression of Shh and Hnf3β in midline. No changes in Shh or its downstream genes in limb bud. |
(91, 170) | |
| Ift88fxo (Ift88hypo) | ENU- mutagenesis, null mutation | Lack nodal cilia | Dies at E12.5. Sharp angle of the mesencephalic flexure, abnormal brain morphology and preaxial polydactyly. |
Disrupted Hh signaling with loss of both Gli activator function and Gli repressor function in the limbs. | (56, 173) | |
| Ift80flox/flox; Prx1-Cre | Deletion in limb mesenchyme | Cilia loss | Severe polydactyly and defects in endochondral bone formation. | Aberrant Shh and Ihh signaling. | (174) | |
| Ift80flox/flox; Msx2-Cre | Deletion in limb ectoderm | Cilia loss | No overt effect on limb patterning. | Not reported. | (174) | |
| Ift80flox/flox; Col2α-Cre | Deletion in committed chondrocyte | Cilia loss | Postnatal dwarfism and premature loss of the growth plate with down-regulated proliferation and up-regulated hypertrophic differentiation of the chondrocytes. Thicker articular cartilage with increased cell density and OA symptoms. | Reduced Hh but elevated Wnt/β-catenin (reduced Sfrp5) signaling. Uprelated Hh signaling in articular cartilage with reduced Gli3 repressor/Gli3 activator. | (93) (176) (175) | |
| Ift172 | Ift172wim | ENU- mutagenesis, a null mutation | Lack nodal cilia | Arrested at E10.5–11.5. Open neural tube in the head that lacked the normal groove on the ventral midline. | Strong defect in Shh signaling. Normal Wnt signaling. |
(56) (178) |
| Ift172avc1 | ENU- mutagenesis, partial loss of function | Defects in cilia | Die at birth. Anomalies in vertebral, trancheoesophageal and limb, defects in cardiac, anal atresia, renal dysplasia and hydrocephalous. | Defects in Hh signaling with reduced Gli3 processing and Gli2 accumulation. | (92) | |
| Ift172Slb | Conventional knockout, a null mutation | Short and without visible microtubules | Die between E12.5 and 13.0. Severe craniofacial malformations, defects in brain patterning, failure to close the neural tube and exencephaly. | Shh and Gli1 decreased in the developing forebrain and midbrain. | (179) | |
| Ift172Δ/Δ | CMV-Cre–mediated germline deletion | Not reported | Embryonic lethality. Neural tube defects (Similar to Ift172wim and 172Slb) |
Not reported | (180) | |
| Ift172f/t; Prx1-Cre | One allele is germline deletion and another is only deleted in the developing limb bud mesenchyme | Not reported | Eight digits on each forelimb and a single extra digit on each hind limb. | Not reported | (180) | |
| Ift20 | Ift20Flox; Prm-Cre | Germline deletion | Not reported | Die before birth | Not reported | (183) |
| Ift25 | Ift25neo and Ift25null1 | Null mutation | Normal cilia | Die at birth. Omphaloceles, polydactyly with a preaxial digit duplication, micrognathia, cleft palate and malalignment of the sternal vertevbrae. | Ciliary accumulation of Shh components and attenuated Shh. | (185) |
| Ngd5 (Ift52) | Ift52hypo | Partial loss-of-function mutations | Not reported | Tight mesencephalic flexure, left-right and ventral midline defects, polydactyly and craniofacial defect. | Defects in Hh pathway in limb buds. | (173) |
| Traf3ip1/MIP-T3 (Ift54) | Traf3ip1GT | Gene Trap | Cilia disrupt | Die before E13.5. Neural developmental defects, cardiac edema and polydactyly. |
Defects in Hh pathway. Unchanged Wnt pathway. Elevated mTor pathway. |
(193) |
| Hippi (Ift57) | Hippi−/− | Conventional knockout | Defects in nodal cilia | Die predominantly prior to E10.5. Defects in left-right patterning and nervous system development. |
Down-regulated Shh pathway. | (196) |