Targeted deletion of the tachykinin 4 gene (TAC4-/-) influences the early stages of B lymphocyte development.
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 the 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 with 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 that supports and regulates the proliferation and differentiation of hematopoietic cells.
Berger
Alexandra
A
Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada. aberger@uhnres.utoronto.ca
Benveniste
Patricia
P
Corfe
Steven A
SA
Tran
Anne H
AH
Barbara
Mary
M
Wakeham
Andrew
A
Mak
Tak W
TW
Iscove
Norman N
NN
Paige
Christopher J
CJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D018390:Gene Targeting; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D066298:In Vitro Techniques; D038041:Lymphopoiesis / Q000235:genetics* / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000276:immunology*; D011498:Protein Precursors / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000235:genetics; D015320:Tachykinins / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology / Q000502:physiology
D017931:DNA Primers; D011498:Protein Precursors; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; C423233:Tac4 protein, mouse; D015320:Tachykinins