Targeted deletion of the tachykinin 4 gene (TAC4-/-) influences the early stages of B lymphocyte development.
Blood 2010 Jul 26; In press
Berger A, Benveniste P, Corfe S SA, Tran A AH, Barbara M, Wakeham A, Mak T TW, Iscove N NN, Paige C CJ
Division of Stem Cell and Developmental Biology, Ontario Cancer Insitute, Princess Margaret Hospital, Toronto, ON, Canada;
Hemokinin-1 (HK-1), encoded by the TAC4 gene, is a tachykinin peptide that is predominantly expressed in non-neuronal cells such as immune cells. We have disrupted the mouse TAC4 gene to obtain a better understanding of the actions of HK-1 during hematopoiesis. We demonstrate here that TAC4(-/-) mice exhibit an increase of CD19(+)CD117(+)HSA(+)BP.1(-) "fraction B" pro-B cells in the bone marrow, whereas pre-B, immature and mature B cells are within normal range. We show that in vitro cultures derived from TAC4(-/-) bone marrow, sorted "fraction B" pro-B cells or purified long-term reconstituting stem cells contain significantly higher numbers of pro-B cells compared to controls, suggesting an inhibitory role for HK-1 on developing B cells. Supporting this idea we show that addition of HK-1 to cultures established from long-term reconstituting stem cells and the newly described intermediate-term reconstituting stem cells leads to a significant decrease of de novo generated pro-B cells. Based on our studies we postulate that HK-1 plays an inhibitory role in hematopoiesis and we hypothesize that it may be part of the bone marrow microenvironment which supports and regulates the proliferation and differentiation of hematopoietic cells.