The Questions of Developmental Biology

The STAT pathway is very important in the regulation of human fetal bone growth.
Mutations that prematurely activate the STAT pathway have been implicated in some severe
forms of dwarfism such as the lethal thanatophoric dysplasia, wherein the growth plates of the
rib and limb bones fail to proliferate. The short-limbed newborn dies because its ribs cannot
support breathing. The genetic lesion resides in the gene encoding fibroblast growth factor
receptor 3 (FGFR3) (Figure 6.22; Rousseau et al. 1994; Shiang et al. 1994). This protein is
expressed in the cartilage precursor cells known as chondrocytes in the growth plates of the
long bones. Normally, the FGFR3 protein is activated by a fibroblast growth factor, and it signals
the chondrocytes to stop dividing and begin differentiating into cartilage. This signal is mediated
by the STAT1 protein, which is phosphorylated by the activated FGFR3 and then translocated
into the nucleus. Inside the nucleus, this transcription factor activates the genes encoding a cell
cycle inhibitor, the p21 protein (Su et al. 1997). The mutations causing thanatophoric dwarfism
result in a gain-of-function phenotype, wherein the mutant FGFR3 is active constitutively that
is, without the need to be activated by an FGF (Deng et al. 1996; Webster and Donoghue 1996).
This causes the chondrocytes to stop proliferating shortly after they are formed, and the bones fail
to grow. Mutations that activate FGFR3 to a lesser degree produce achondroplasic (short-limbed)
dwarfism, the most prevalent human dominant syndrome.