A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos

Abstract

We have generated the first mouse model of fibro-blast growth factor receptor 3 (Fgfr3) with the K644E mutation, which accurately reflects the embryonic onset of a neonatal lethal dwarfism, thanatophoric dysplasia type II (TDII). Long-bone abnormalities were identified as early as embryonic day 14, during initiation of endochondral ossification. Increased expression of PATCHED: (PTC:) was observed, independent of unaltered expression of parathyroid hormone-related peptide (PTHrP) receptor and Indian Hedgehog (IHH:), suggesting a new regulatory role for Fgfr3 in embryos. We demonstrate that the mutation enhances chondrocyte proliferation during the early embryonic skeletal development, in contrast to previous reports that showed decreased proliferation in postnatal-onset dwarf mice with activating Fgfr3 mutations. This suggests that signaling through Fgfr3 both promotes and inhibits chondrocyte proliferation, depending on the time during development. In contrast, suppressed chondrocyte differentiation was observed throughout the embryonic stages, defining decreased differentiation as the primary cause of retarded longitudinal bone growth in TDII. This model was successfully crossed with a cartilage-specific CRE: transgenic strain, excluding the lung as the primary cause of lethality.

Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

“…Many of the common forms of dwarfim are caused by activating mutations in Fgfr3 (Naski et al, 1998), suggesting that in the growth plate of long bones, FGFR3 is a negative regulator of chondrocyte proliferation. However, Iwata et al reported that signaling through FGFR3 can both promote and inhibit chondrocyte proliferation depending on the stage of development (Iwata et al, 2000). FGF-18 signaling through FGFR3 may enhance chondrocyte proliferation in immature committed chondrocytes, even though it is well established that signaling through FGFR3 inhibits chondrocyte proliferation and differentiation in the mature proliferating chondrocyte zone of the growth plate (Ellsworth et al, 2002;Liu et al, 2002).…”

Indian hedgehog: Its roles and regulation in endochondral bone development

“…FGFs bind to and activate this receptor and cause growth arrest in chondrocytes, leading to short limbs. Early studies also suggested that FGFs inhibit chondrocyte differentiation [Iwata et al, 2000], although this hypothesis has been challenged by more recent studies. Minina et al [2002] using an organ culture from embryonic limb explants, has demonstrated that FGF2 reduced the rate of chondrocyte proliferation, as well as promoting chondrocyte hypertrophic differentiation as indicated by the shorter distance between the joint and hypertrophic chondrocytes.…”

Fibroblast growth factor receptor 2 (Fgfr2) plays an important role in eyelid and skin formation and patterning

“…Fgfr3-null mice are viable, however they exhibited prolonged and faster growth of long bones (Colvin et al, 1996;Deng et al, 1997). Conversely, introduction of constitutively activated mutations into Fgfr3 results in dominant dwarfism due to retarded long bone growth (Chen et al, , 2001Iwata et al, 2000;Li et al, 1999). Fgfr4-null mice exhibit depleted gallbladders and have elevated cholesterol metabolism and bile acid synthesis (Yu et al, 2000a).…”