Morpholinos for splice modificatio

Morpholinos for splice modification


Conditional ablation of Pten in osteoprogenitors stimulates FGF signaling
Anyonya R. Guntur, Martina I. Reinhold, Joe Cuellar, Jr, Michael C. Naski


Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a direct antagonist of phosphatidylinositol 3 kinase. Pten is a well recognized tumor suppressor and is one of the most commonly mutated genes in human malignancies. More recent studies of development and stem cell behavior have shown that PTEN regulates the growth and differentiation of progenitor cells. Significantly, PTEN is found in osteoprogenitor cells that give rise to bone-forming osteoblasts; however, the role of PTEN in bone development is incompletely understood. To define how PTEN functions in osteoprogenitors during bone development, we conditionally deleted Pten in mice using the cre-deleter strain Dermo1cre, which targets undifferentiated mesenchyme destined to form bone. Deletion of Pten in osteoprogenitor cells led to increased numbers of osteoblasts and expanded bone matrix. Significantly, osteoblast development and synthesis of osteoid in the nascent bone collar was uncoupled from the usual tight linkage to chondrocyte differentiation in the epiphyseal growth plate. The expansion of osteoblasts and osteoprogenitors was found to be due to augmented FGF signaling as evidenced by (1) increased expression of FGF18, a potent osteoblast mitogen, and (2) decreased expression of SPRY2, a repressor of FGF signaling. The differentiation of osteoblasts was autonomous from the growth plate chondrocytes and was correlated with an increase in the protein levels of GLI2, a transcription factor that is a major mediator of hedgehog signaling. We provide evidence that increased GLI2 activity is also a consequence of increased FGF signaling through downstream events requiring mitogen-activated protein kinases. To test whether FGF signaling is required for the effects of Pten deletion, we deleted one allele of fibroblast growth factor receptor 2 (FGFR2). Significantly, deletion of FGFR2 caused a partial rescue of the Pten-null phenotype. This study identifies activated FGF signaling as the major mediator of Pten deletion in osteoprogenitors.

  • Accepted January 6, 2011.
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