Further Development 4.9: The JAK and STAT of Bone Development

Cell-to-Cell Communication: Mechanisms of Morphogenesis

The JAK-STAT pathway is critically important in regulating human fetal bone growth. Mutations that prem-aturely activate the STAT pathway have been implicated in some severe forms of dwarfism, such as the lethal condition thanatophoric dysplasia, in which 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 responsible is in FGFR3, the gene encoding fibroblast growth factor receptor 3 (Figure 1; Rousseau et al. 1994; Shiang et al. 1994). FGFR3 is expressed in the cartilage-forming cells (chondrocytes) of the growth plates of the long bones. Normally, activated FgfR3 (bound with an FGF ligand) signals the chondrocytes to control the ex-pansion of the growth plate. This signal is mediated by phosphorylation of the Stat1 protein, which then trans-locates into the nucleus. Inside the nucleus, Stat1 activates the genes encoding a cell cycle inhibitor, the p21 protein (Su et al. 1997). The mutations causing thanatophoric dwarfism result from a gain-of-function muta-tion in the FGFR3 gene. The mutant receptor gene is active constitutively; that is, it is without the need to be activated by an FGF signal (Deng et al. 1996; Webster and Donoghue 1996). Chondrocytes in the growth plates stop dividing prematurely and the bones fail to grow. Other mutations that activate FGFR3 prematurely but to a lesser degree produce achondroplasic (short-limbed) dwarfism (Legeai-Mallet et al. 2004).

Figure 1A mutation in the gene for FgfR3 causes the premature constitutive activation of the STAT pathway and the production of phosphorylated Stat1 protein. This transcription factor activates genes that cause the premature termination of chondrocyte cell division in the growth plates. The result is thana-tophoric dysplasia, a condition of failed bone growth that results in the death of the newborn infant because the thoracic cage cannot expand to allow breathing.

Literature Cited

Deng, C., A. Wynshaw-Boris, F. Zhou, A. Kuo and P. Leder. 1996. Fibroblast growth factor receptor-3 is a negative regulator of bone growth. Cell 84: 911–921.
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Legeai-Mallet, L., C. Benoist-Lasselin, A. Munnich and J. Bonaventure. 2004. Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias. Bone 34: 26–36.
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Rousseau, F., J. Bonaventure, L. Legeai-Mallet, A. Pelet, J. M. Rozet, P. Maroteaux, M. Le Merrer and A. Munnich. 1994. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondropla-sia. Nature 371: 252–254.
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Shiang, R., L. M. Thompson, Y. Z. Zhu, D. M. Church, T. J. Fielder, M. Bocian, S. T. Winokur and J. J. Was-muth. 1994. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78: 335–342.
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Su, W.-C. S., M. Kitagawa, N. Xue, B. Xie, S. Garofalo, J. Cho, C. Deng, W. A. Horton and X. Y. Fu. 1997. Acti-vation of Stat1 by mutant fibroblast growth factor receptor in thanatophoric dysplasia type II dwarf-ism. Nature 386: 288–292.
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Webster, M. K. and D. J. Donoghue. 1996. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 15: 520–527.
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