CONTROL OF LYMPHOPOIESIS BY P50(CSK), A REGULATORY PROTEIN-TYROSINE KINASE

The csk gene encodes a nonreceptor protein tyrosine kinase that acts in part by regulating the activity of src-family protein tyrosine kinases. Since the src-family kinases p56(lck) and p59(fyn) play pivotal roles during lymphocyte development, it seemed plausible that p50(csk) might contribute to these regulatory circuits. Using a gene targeting approach, mouse embryonic stem cell lines lacking functional csk genes were generated. These csk(null) embryonic stem cells proved capable of contributing to many adult tissues, notably heart and brain. However, although csk(null) progenitors colonized the developing thymus, T and B cell differentiation were both blocked at very early stages. This represented a relatively selective interdiction of lymphocyte maturation, since csk(null) hematopoietic progenitors supported the development of normal-appearing MAC-1(+) blood leukocytes, and the successful maturation of granulocyte/macrophage-colony-forming units from fetal liver progenitors. We conclude that p50(csk) regulates normal lymphocyte differentiation, but that it almost certainly does so by acting on targets other than p56(kk) and p59(fyn).