Tyrosine phosphatase SHP-1 acts at different stages of development to regulate hematopoiesis

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Abstract
Mice lacking SHP-1 exhibit a plethora of perturbations in their hematopoietic and immune systems. To reveal the primary effects resulting from SHP-1 deficiency, we used embryonic stem (ES) cells to study the role of SHP-1 in developmental hematopoiesis. We expressed wild-type (WT) and dominant-negative (R459M) forms of SHP-1 in ES cells and used ES/OP-9 coculture and embryoid body development followed by hematopoietic colony assays to demonstrate that SHP-1 acts at multiple stages of hematopoietic differentiation to alter lineage balance. Expression of WT SHP-1 reduced myeloid colony numbers while increasing the numbers of secondary embryoid bodies and mixed hematopoietic colonies obtained. Conversely, expression of R459M SHP-1 resulted in a significant increase in the numbers and sizes of myeloid colonies observed while reducing the numbers of colonies derived from undifferentiated cells or hematopoietic precursor cells. Confining the expression of WT or R459M SHP-1 to the early phases of differentiation decreased and increased progenitor cell numbers, respectively, and influenced colony formation. Overall, our results are consistent with SHP-1 acting during multiple stages of hematopoietic development, and they suggest that the increases in granulocytes and macrophages observed in motheaten mice arise as the result of a cell autonomous effect early during development.